Chimeric receptors and methods of use thereof

Abstract

The present disclosure is related to compositions that include polynucleotides encoding chimeric receptors, methods of delivering polynucleotides encoding chimeric receptors to immune cells, and methods of using immune cells encoding chimeric receptors to treat or prevent cancer.

What is claimed is: 
     
         1 . A polynucleotide encoding a chimeric receptor, wherein the chimeric receptor comprises:
 (1) an extracellular ligand-binding domain, wherein the ligand is an agent associated with cancer;   (2) a transmembrane domain; and   (3) a signaling domain,   wherein binding of the ligand to the chimeric receptor expressed in an innate immune cell activates the signaling domain, and the activated signaling domain induces and/or enhances (i) an M1 phenotype in the innate immune cell, (ii) secretion of one or more pro-inflammatory cytokines from the innate immune cell, (iii) the innate immune cell's activity in inhibiting an immune checkpoint molecule, (iv) the innate immune cell's activity in inhibiting myeloid derived suppressor cell (MDSC) suppressor signaling, (v) the innate immune cell's activity in inducing cytotoxic T cell (CTL) activation, (vi) the innate immune cell's activity in depressing a T cell, or any combination thereof.   
     
     
         2 . The polynucleotide of  claim 1 , wherein the polynucleotide comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 27-33. 
     
     
         3 . An isolated polynucleotide encoding a chimeric receptor, wherein the polynucleotide comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 27-33. 
     
     
         4 . The polynucleotide of any one of  claims 1 - 3 , wherein the chimeric receptor comprises an amino acid sequence selected form the group consisting of SEQ ID Nos: 20-26. 
     
     
         5 . The polynucleotide of any one of  claims 1 - 4 , wherein the ligand-binding domain is selected from the group consisting of a single-domain antibody, a nanobody, a heavy-chain antibody, a V NAR  fragment, a single-chain Fv domain (scFv), a V L  domain linked to a V H  domain by a flexible linker, an antibody Fab, and an extracellular domain of a receptor. 
     
     
         6 . The polynucleotide of any one of  claims 1 - 5 , wherein the agent associated with cancer is a tumor antigen. 
     
     
         7 . The polynucleotide of any one of  claims 6 , wherein the tumor antigen is selected from the group consisting of CD19, CD20, CD22, ROR1, mesothelin, CD33/IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIII, GD-2, NY-ESO-1, and MAGE A3. 
     
     
         8 . The polynucleotide of any one of  claims 1 - 4 , wherein the ligand-binding domain is a CD19 single-chain variable fragment (scFv) domain. 
     
     
         9 . The polynucleotide of any one of  claims 1 - 8 , wherein the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, myeloid-derived tumors, thyroid cancer, and any combination thereof. 
     
     
         10 . The polynucleotide of any one of  claims 1 - 9 , wherein the transmembrane domain is a transmembrane domain from a protein selected from the group consisting of a receptor tyrosine kinase (RTK), an M-CSF receptor, CSF-1R, Kit, TIE3, an ITAM-containing protein, DAP12, DAP10, an Fc receptor, FcR-gamma, FcR-epsilon, FcR-beta, TCR-zeta, CD3-gamma, CD3-delta, CD3-epsilon, CD3-zeta, CD3-eta, CD5, CD22, CD79a, CD79b, CD66d, TNF-alpha, NF-kappaB, a TLR (toll-like receptor), TLR5, Myd88, lymphocyte receptor chain, IL-2 receptor, IgE, IgG, CD16α, FcγRIII, FcγRII, CD28, 4-1BB, CD4, and CD8. 
     
     
         11 . The polynucleotide of any one of  claims 1 - 9 , wherein the transmembrane domain is a transmembrane domain selected from the group consisting of a CD8 transmembrane domain, a DAP12 transmembrane domain, a CASF-1R transmembrane domain, and a TLR5 transmembrane domain. 
     
     
         12 . The polynucleotide of any one of  claims 1 - 11 , wherein the signaling domain is a signaling domain selected from the group consisting of a 4-1BB intracellular domain, a CSF-1R receptor tyrosine kinase (RTK) intracellular domain, a TLR5 intracellular domain, a CD28 intracellular domain, and any combination thereof. 
     
     
         13 . The polynucleotide of any one of  claims 1 - 12 , wherein the innate immune cell is an innate immune cell selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, neutrophils, activated neutrophils, NK cells, dendritic cells, monocytes, osteoclasts, Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, M2 microglia, astrocytes, A1 astrocytes, A2 astrocytes, and any combination thereof. 
     
     
         14 . The polynucleotide of any one of  claims 1 - 12 , wherein the innate immune cell is a myeloid cell. 
     
     
         15 . The polynucleotide of any one of  claims 1 - 14 , wherein the chimeric receptor further comprises one or more additional signaling domains. 
     
     
         16 . The polynucleotide of  claim 15 , wherein the one or more additional signaling domains comprise a signaling domain from one or more proteins selected from the group consisting of a receptor tyrosine kinase (RTK), an M-CSF receptor, CSF-1R, Kit, TIE3, DAP12, DAP10, an Fc receptor, FcR-gamma, FcR-epsilon, FcR-beta, TCR-zeta, CD3-gamma, CD3-delta, CD3-epsilon, CD3-zeta, CD3-eta, CD5, CD22, CD79a, CD79b, CD66d, TNF-alpha, NF-KappaB, a TLR (toll-like receptor), TLRS, Myd88, TOR/CD3 complex, lymphocyte receptor chain, IL-2 receptor, IgE, IgG, CD16α, FcγRIII, FcγRII, CD28, 4-1BB, and any combination thereof. 
     
     
         17 . The polynucleotide of  claim 15 , wherein the one or more additional signaling domains comprise a signaling domain selected from the group consisting of a CD3-zeta ITAM domain, a CD3-zeta intracellular domain, a DAP12 intracellular domain, a TCR-zeta intracellular domain, a DAP10 intracellular domain, an FcR-gamma intracellular domain, and any combination thereof. 
     
     
         18 . The polynucleotide of any one of  claims 1 - 17 , wherein the chimeric receptor further comprises a flexible linker located between the transmembrane domain and the signaling domain. 
     
     
         19 . The polynucleotide of  claim 18 , wherein the flexible linker is a flexible linker selected from the group consisting of a CD8 hinge domain, a TLRS hinge domain, and a CSF-1R linker domain. 
     
     
         20 . The polynucleotide of any one of  claims 1 - 19 , wherein the chimeric receptor further comprises a signal peptide at the N-terminus of the chimeric receptor. 
     
     
         21 . The polynucleotide of  claim 20 , wherein the signal peptide is a CD8 secretory signal peptide. 
     
     
         22 . The polynucleotide of any one of  claims 1 - 21 , wherein the chimeric receptor further comprises a heterodimerization domain. 
     
     
         23 . The polynucleotide of  claim 22 , wherein the heterodimerization domain is an inducible heterodimerization domain. 
     
     
         24 . The polynucleotide of  claim 23 , wherein the heterodimerization domain is a FK506 binding protein (FKBP) heterodimerization domain. 
     
     
         25 . The polynucleotide of  claim 23 , wherein the heterodimerization domain is a T2089L mutant of FKBP-rapamycin binding domain (FRB*) heterodimerization domain. 
     
     
         26 . The polynucleotide of any one of  claims 1 - 25 , wherein binding of the ligand to the chimeric receptor expressed in the innate immune cell induces one or more innate immune cell activities selected from the group consisting of:
 a. TREM1 phosphorylation;   b. DAP12 phosphorylation;   c. activation of one or more tyrosine kinases;   d. activation of phosphatidylinositol 3-kinase (PI3K);   e. activation of protein kinase B;   f. recruitment of phospholipase C-gamma (PLC-gamma) to a cellular plasma membrane, activation of PLC-gamma, or both;   g. recruitment of TEC-family kinase dVav to a cellularplasma membrane;   h. activation of nuclear factor-rB (NF-rB);   i. inhibition of MAPK signaling;   j. phosphorylation of linker for activation of T cells (LAT), linker for activation of B cells (LAB), or both;   k. activation of IL-2-induced tyrosine kinase (Itk);   l. modulation of one or more pro-inflammatory mediators selected from the group consisting of IFN-γ, IL-1α, IL-1β, TNF-α, IL-6, IL-8, CRP, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, IL-23, CXCL10, MCP-1, and any combination thereof;   m. modulation of one or more anti-inflammatory mediators selected from the group consisting of IL-4, IL-10, TGF-β, IL-13, IL-35, IL-16, IFN-α, IL-1Rα, VEGF, G-CSF, soluble receptors for TNF, soluble receptors for IL-6, and any combination thereof;   n. phosphorylation of extracellular signal-regulated kinase (ERK);   o. modulated expression of C—C chemokine receptor 7 (CCR7);   p. induction of microglial cell chemotaxis toward CCL19 and CCL21 expressing cells;   q. normalization of disrupted ITAM-dependent gene expression;   r. recruitment of Syk, ZAP70, or both to an ITAM complex;   s. increased activity of one or more ITAM-dependent genes or CSF-1R-dependent genes;   t. increased maturation of dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, astrocytes, A1 astrocytes, A2 astrocytes, or any combination thereof;   u. increased ability of dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, astrocytes, A1 astrocytes, A2 astrocytes, or any combination thereof to prime or modulate the function of T cells;   v. enhanced ability, normalized ability, or both of bone marrow-derived dendritic cells to prime or modulate function of antigen-specific T cells;   w. induction of osteoclast production, increased rate of osteoclastogenesis, or both;   x. increased survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, M2 microglia, Astrocytes, A1 astrocytes, A2 astrocytes, or any combination thereof;   y. increased function of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, microglia, M1 microglia, activated M1 microglia, M2 microglia, astrocytes, A1 astrocytes, A2 astrocytes, or any combination thereof;   z. increasing phagocytosis by dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, microglia, M1 microglia, activated M1 microglia, M2 microglia, astrocytes, A1 astrocytes, A2 astrocytes, or any combination thereof;   aa. induction of one or more types of clearance selected from the group consisting of apoptotic neuron clearance, nerve tissue debris clearance, non-nerve tissue debris clearance, bacteria clearance, other foreign body clearance, disease-causing protein clearance, disease-causing peptide clearance, disease-causing nucleic acid clearance, tumor cell clearance, and any combination thereof;   bb. induction of phagocytosis of one or more of apoptotic neurons, nerve tissue debris, non-nerve tissue debris, dysfunctional synapses, bacteria, other foreign bodies, disease-causing proteins, disease-causing peptides, disease-causing nucleic acids, tumor cells, or any combination thereof;   cc. increased expression of one or more stimulatory molecules selected from the group consisting of CD83, CD86 MHC class II, CD40, and any combination thereof;   dd. modulated expression of one or more proteins selected from the group consisting of C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, PYCARD, VEGF, and any combination thereof;   ee. activation of tumor cell killing by one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, or any combination thereof;   ff. activating anti-tumor cell proliferation activity of one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, or any combination thereof;   gg. activating anti-tumor cell metastasis activity of one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, or any combination thereof;   hh. decreasing tumor volume;   ii. decreasing tumor growth rate; and   jj. increasing efficacy of one or more immune-therapies that modulate anti-tumor T cell responses, optionally wherein the one or more immune-therapies are selected from PD1/PDL1 blockade, CTLA-4 blockade, and cancer vaccines.   
     
     
         27 . The polynucleotide of any one of  claims 1 - 26 , wherein the polynucleotide is a DNA polynucleotide. 
     
     
         28 . The polynucleotide of any one of  claims 1 - 26 , wherein the polynucleotide is an RNA polynucleotide. 
     
     
         29 . A vector comprising the polynucleotide of any one of  claims 1 - 28 . 
     
     
         30 . The vector of  claim 29 , wherein the vector is a lentiviral vector, a retroviral vector, a sleeping beauty vector, an AAV vector, or a non-viral plasmid vector. 
     
     
         31 . An isolated chimeric receptor encoded by the polynucleotide of any one of  claims 1 - 28 . 
     
     
         32 . An isolated innate immune cell comprising the polynucleotide of any one of  claims 1 - 28 . 
     
     
         33 . An isolated innate immune cell comprising the vector of  claim 29  or  claim 30 . 
     
     
         34 . An isolated innate immune cell comprising the chimeric receptor of any one of  claim 31 . 
     
     
         35 . The isolated innate immune of any one of  claims 32 - 34 , wherein the cell is a myeloid cell. 
     
     
         36 . The innate immune cell of any one of  claims 32 - 34 , wherein the cell is selected from the group consisting of a macrophage, an M1 macrophage, an activated M1 macrophage, an M2 macrophage, a neutrophil, a NK cell, a dendritic cell, a monocyte, an osteoclast, a Langerhans cell, a Kupffer cell, a microglial cell, an M1 microglial cell, an activated M1 microglial cell, an M2 microglial cell, an astrocyte, an A1 astrocyte, and an A2 astrocyte. 
     
     
         37 . The isolated innate immune cell of any one of  claims 32 - 36 , wherein the cell lacks one or more genes encoding one or more immune molecules that allow for recognition by the adaptive immune system. 
     
     
         38 . The isolated innate immune cell of  claim 37 , wherein the one or more immune molecules are MHC class I molecules, MHC class I co-receptors, MHC class II molecules, MHC class II co-receptors, or any combination thereof. 
     
     
         39 . The isolated innate immune cell of  claim 37  or  claim 38 , wherein the one or more genes were deleted using a nuclease selected from the group consisting of a Cas9 nuclease, a TALEN, and a ZFN. 
     
     
         40 . An isolated myeloid cell expressing the chimeric receptor of  claim 31 , wherein the cell phenotype is modified in vitro or in vivo by addition of one or more of GM-CSF, MCSF, IL-1, IL-4, IL-10, IL-12, TNF-α, TGF-beta, LPS, or any combination thereof. 
     
     
         41 . A method of producing an innate immune cell expressing a chimeric receptor, comprising:
 (a) isolating an innate immune cell;   (b) introducing the vector of  claim 29  or  claim 30  into the cell; and   (c) culturing the cell so that the chimeric receptor is expressed.   
     
     
         42 . The method of  claim 41 , wherein the innate immune cell is a myeloid cell. 
     
     
         43 . The method of  claim 41 , wherein the innate immune cell is selected from the group consisting of a macrophage, an M1 macrophage, an activated M1 macrophage, an M2 macrophage, a neutrophil, a NK cell, a dendritic cell, a monocyte, an osteoclast, a Langerhans cell, a Kupffer cell, a microglial cell, an M1 microglial cell, an activated M1 microglial cell, an M2 microglial cell, an astrocyte, an A1 astrocyte, and an A2 astrocyte. 
     
     
         44 . An isolated innate immune cell comprising a chimeric receptor produced by the method of any one of  claims 41 - 43 . 
     
     
         45 . The isolated cell of any one of  claims 32 - 40  and  44 , wherein the cell further expresses one or more signaling factors that promote an M2 phenotype by inhibiting a TNF-alpha/NF-KappaB pathway a TLR/MyD88 pathway, or both. 
     
     
         46 . The isolated cell of  claim 45 , wherein the one or more signaling factors that promote an M2 phenotype by inhibiting a TNF-alpha/NF-KappaB pathway are selected from the group consisting of a dominant negative IKK-alpha, a dominant negative IKK-alpha IKK-beta, a dominant negative IKK-alpha IKBa (IKBa-DN), a MEKK isoform, and any combination thereof. 
     
     
         47 . The isolated cell of  claim 45  or  claim 46 , wherein the one or more signaling factors that promote an M2 phenotype by inhibiting a TLR/MyD88 pathway are one or more dominant negative forms of MyD88. 
     
     
         48 . A pharmaceutical composition comprising the polynucleotide of any one of  claims 1 - 28 , and a pharmaceutically acceptable carrier. 
     
     
         49 . A pharmaceutical composition comprising the vector of  claim 29  or  claim 30 , and a pharmaceutically acceptable carrier. 
     
     
         50 . A pharmaceutical composition comprising the chimeric receptor of  claim 31 , and a pharmaceutically acceptable carrier. 
     
     
         51 . A pharmaceutical composition comprising the isolated cell of any one of  claims 32 - 40  and  44 - 47 , and a pharmaceutically acceptable carrier. 
     
     
         52 . A method of preventing, reducing risk, or treating cancer, comprising administering to an individual in need thereof a therapeutically effective amount of the isolated cell of any one of  claims 32 - 40 , and  44 - 47 . 
     
     
         53 . A method of preventing, reducing risk, or treating cancer in an individual in need thereof, comprising:
 (a) obtaining a plurality of isolated innate immune cells;   (b) introducing the vector of  claim 29  or  claim 30  into the plurality of isolated innate immune cells; and   (c) administering to the individual a therapeutically effective amount of the plurality of isolated innate immune cells containing the vector.   
     
     
         54 . The method of  claim 52  or  claim 53 , wherein binding of the ligand to the chimeric receptor expressed in the cell induces an increase in myeloid cell activation, proliferation, survival, phagocytosis, and/or functionality. 
     
     
         55 . The method of any one of  claims 52 - 54 , wherein the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, myeloid-derived tumors, thyroid cancer, and any combination thereof. 
     
     
         56 . The method of any one of  claims 52 - 55 , wherein the cells are selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, neutrophils, NK cells, dendritic cells, monocytes, osteoclasts, Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, M2 microglia, astrocytes, A1 astrocytes, A2 astrocytes, and any combination thereof. 
     
     
         57 . The method of any one of  claims 52 - 56 , wherein the administering induces one or more activities selected from the group consisting of:
 a. TREM1 phosphorylation;   b. DAP12 phosphorylation;   c. activation of one or more tyrosine kinases;   d. activation of phosphatidylinositol 3-kinase (PI3K);   e. activation of protein kinase B;   f. recruitment of phospholipase C-gamma (PLC-gamma) to a cellular plasma membrane, activation of PLC-gamma, or both;   g. recruitment of TEC-family kinase dVav to a cellular plasma membrane;   h. activation of nuclear factor-rB (NF-rB);   i. inhibition of MARK signaling;   j. phosphorylation of linker for activation of T cells (LAT), linker for activation of B cells (LAB), or both;   k. activation of IL-2-induced tyrosine kinase (Ilk);   l. modulation of one or more pro-inflammatory mediators selected from the group consisting of IFN-γ, IL-1α, IL-1β, TNF-α, IL-6, IL-8, CRP, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, IL-23, CXCL10, MCP-1, and any combination thereof;   m. modulation of one or more anti-inflammatory mediators selected from the group consisting of IL-4, IL-10, TGF-β, IL-13, IL-35, IL-16, IFN-α, IL-1Rα, VEGF, G-CSF, soluble receptors for TNF, soluble receptors for IL-6, and any combination thereof;   n. phosphorylation of extracellular signal-regulated kinase (ERK);   o. modulated expression of C—C chemokine receptor 7 (CCR7);   p. induction of microglial cell chemotaxis toward CCL19 and CCL21 expressing cells;   q. normalization of disrupted ITAM-dependent gene expression;   r. recruitment of Syk, ZAP70, or both to an ITAM complex;   s. increased activity of one or more ITAM-dependent genes or CSF-1R-dependent genes;   t. increased maturation of dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, astrocytes, A1 astrocytes, A2 astrocytes, or any combination thereof;   u. increased ability of dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, astrocytes, A1 astrocytes, A2 astrocytes, or any combination thereof to prime or modulate the function of T cells;   v. enhanced ability, normalized ability, or both of bone marrow-derived dendritic cells to prime or modulate function of antigen-specific T cells;   w. induction of osteoclast production, increased rate of osteoclastogenesis, or both;   x. increased survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, M2 microglia, Astrocytes, A1 astrocytes, A2 astrocytes, or any combination thereof;   y. increased function of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, microglia, M1 microglia, activated M1 microglia, M2 microglia, astrocytes, A1 astrocytes, A2 astrocytes, or any combination thereof;   z. increasing phagocytosis by dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, microglia, M1 microglia, activated M1 microglia, M2 microglia, astrocytes, A1 astrocytes, A2 astrocytes, or any combination thereof;   aa. induction of one or more types of clearance selected from the group consisting of apoptotic neuron clearance, nerve tissue debris clearance, non-nerve tissue debris clearance, bacteria clearance, other foreign body clearance, disease-causing protein clearance, disease-causing peptide clearance, disease-causing nucleic acid clearance, tumor cell clearance, and any combination thereof;   bb. induction of phagocytosis of one or more of apoptotic neurons, nerve tissue debris, non-nerve tissue debris, dysfunctional synapses, bacteria, other foreign bodies, disease-causing proteins, disease-causing peptides, disease-causing nucleic acids, tumor cells, or any combination thereof;   cc. increased expression of one or more stimulatory molecules selected from the group consisting of CD83, CD86 MHC class II, CD40, and any combination thereof;   dd. modulated expression of one or more proteins selected from the group consisting of C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, PYCARD, VEGF, and any combination thereof;   ee. activation of tumor cell killing by one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, or any combination thereof;   ff. activating anti-tumor cell proliferation activity of one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, or any combination thereof;   gg. activating anti-tumor cell metastasis activity of one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, or any combination thereof;   hh. decreasing tumor volume;   ii. decreasing tumor growth rate; and   jj. increasing efficacy of one or more immune-therapies that modulate anti-tumor T cell responses, optionally wherein the one or more immune-therapies are selected from PD1/PDL1 blockade, CTLA-4 blockade, and cancer vaccines.   
     
     
         58 . The method of any one of  claims 52 - 57 , further comprising administering to the individual at least one antibody that specifically binds to an inhibitory checkpoint molecule, and/or one or more standard or investigational anti-cancer therapies. 
     
     
         59 . The method of  claim 58 , wherein the at least one antibody that specifically binds to an inhibitory checkpoint molecule is administered in combination with the cells. 
     
     
         60 . The method of  claim 58  or  claim 59 , wherein the at least one antibody that specifically binds to an inhibitory checkpoint molecule is selected from the group consisting of an anti-PD-L1 antibody, an anti-CTLA4 antibody, an anti-PD-L2 antibody, an anti-PD-1 antibody, an anti-B7-H3 antibody, an anti-B7-H4 antibody, and anti-HVEM antibody, an anti-B- and T-lymphocyte attenuator (BTLA) antibody, an anti-Killer inhibitory receptor (KIR) antibody, an anti-GALS antibody, an anti-TIM3 antibody, an anti-AZAR antibody, an anti-LAG-3 antibody, an anti-phosphatidylserine antibody, an anti-CD27 antibody, an anti-TNF-α antibody,
 an anti-CD33 antibody, an anti-Siglec-5 antibody, an anti-Siglec-7 antibody, an anti-Siglec-9 antibody, an anti-Siglec-11 antibody, an antagonistic anti-TREM1 antibody, an antagonistic anti-TREM2 antibody, and any combination thereof. 
 
     
     
         61 . The method of  claim 58 , wherein the one or more standard or investigational anti-cancer therapies are selected from the group consisting of radiotherapy, cytotoxic chemotherapy, targeted therapy, imatinib therapy, trastuzumab therapy, etanercept therapy, adoptive cell transfer (ACT) therapy, chimeric antigen receptor T cell transfer (CAR-T) therapy, vaccine therapy, and cytokine therapy. 
     
     
         62 . The method of any one of  claims 52 - 61 , further comprising administering to the individual at least one antibody that specifically binds to an inhibitory cytokine. 
     
     
         63 . The method of  claim 62 , wherein the at least one antibody that specifically binds to an inhibitory cytokine is administered in combination with the cells. 
     
     
         64 . The method of  claim 62  or  claim 63 , wherein the at least one antibody that specifically binds to an inhibitory cytokine is selected from the group consisting of an anti-CCL2 antibody, an anti-CSF-1 antibody, an anti-IL-2 antibody, and any combination thereof. 
     
     
         65 . The method of any one of  claims 52 - 64 , further comprising administering to the individual at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein. 
     
     
         66 . The method of  claim 65 , wherein the at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein is administered in combination with the cells. 
     
     
         67 . The method of  claim 65  or  claim 66 , wherein the at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein is selected from the group consisting of an agonist anti-CD40 antibody, an agonist anti-OX40 antibody, an agonist anti-ICOS antibody, an agonist anti-CD28 antibody, an agonistic anti-TREM1 antibody, an agonistic anti-TREM2 antibody, an agonist anti-CD137/4-1BB antibody, an agonist anti-CD27 antibody, an agonist anti-glucocorticoid-induced TNFR-related protein GITR antibody, and any combination thereof. 
     
     
         68 . The method of any one of  claims 52 - 67 , further comprising administering to the individual at least one stimulatory cytokine. 
     
     
         69 . The method of  claim 68 , wherein the at least one stimulatory cytokine is administered in combination with the cells. 
     
     
         70 . The method of  claim 68  or  claim 69 , wherein the at least one stimulatory cytokine is selected from the group consisting of IFN-a4, IFN-b, IL-1β, TNF-α, IL-6, IL-8, CRP, IL-20 family members, LIF, IFN-gamma, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, IL-23, CXCL10, IL-33, MCP-1, MIP-1-beta, and any combination thereof.