Biomarkers for cancer immunotherapy outcomes

Abstract

Provided herein, inter alia, are improved methods and systems of determining immunotherapy response in subjects prior and during treatment. Provided herein are methods of detecting gene expression in T cells and in monocytes as well as measuring relative abundance of particular immune cell populations and determining responsiveness to anticancer immunotherapy.

1 - 35 . (canceled) 
     
     
         36 . A method of detecting a parameter in a sample of peripheral blood from a subject with cancer, the method comprising detecting:
 (i) gene expression in monocytes comprising:
 (1) increased expression of TNF, FOS, JUN, JUNB, TNFAIP2, TNFAIP3, NFKB1, NFKBIA, NFKBIZ, or a combination of two or more thereof, compared to a control; 
 (2) decreased expression of IKBKB, compared to a control; 
 (3) increased expression of MYD88, compared to a control; or 
   (ii) a greater number of CD8+ differentiated cells, a greater number of CD4+ naive cells, fewer CD4+ differentiated cells, and fewer T follicular helper cells, compared to a control;   (iii) a lower density of total peripheral blood mononuclear cells, a lower density of CD4+ effector memory cells, and a higher density of classical monocytes, compared to a control;   (iv) gene expression in T cells comprising:
 (1) increased expression of IFIT1/3, IFITM3, IFI44L, PSME2, IFI6, ISG15, or a combination of two or more thereof, compared to a control; 
 (2) increased expression of NFKB1, MYD88, NFKBIA, NFKBIZ, or a combination of two or more thereof, compared to a control; 
 (3) increased expression of PIK3CD, PSMA7, PSMB8, PSMD9, HLA-A, HLA-B, HLA-C, HLA-DQB1, HLA-DQA1, HLA-DPB1, HLA-DPA1, HLA-DRB1, HLA-DRA, HLA-DMB, HLA-DMA, or a combination of two or more thereof, compared to a control; 
 (4) increased expression of CCL3, CCL4, CCL5, CCR5, or a combination of two or more thereof, compared to a control; 
 (5) decreased expression of CXCR3, CCR2, or a combination thereof, compared to a control; 
 (6) increased expression in CD8+ T cells in a cell death gene selected from the group consisting of CASP1, CASP3, CASP7, CASP8, and a combination of two or more thereof, compared to a control; 
 (7) a greater number of differentiated CD8+ cells, compared to a control; or 
 (8) fewer differentiated CD4+ cells compared to a control; or 
   (v) gene expression in monocytes comprising:
 (1) increased expression of genes upregulated by IFN stimulation, compared to a control; or 
 (2) increased expression of genes upregulated by major histocompatibility complex 2 (MCHII) production, compared to a control. 
   
     
     
         37 . The method of  claim 36 , wherein the cancer is a gastrointestinal cancer. 
     
     
         38 . The method of  claim 36 , wherein the cancer is colorectal cancer, gastroesophageal cancer, pancreatic cancer, or biliary cancer. 
     
     
         39 . The method of  claim 36 , wherein the subject was previously treated with a PD-1 inhibitor. 
     
     
         40 . The method of  claim 36 , wherein detecting gene expression comprises single-cell RNA sequencing, single sample gene set enrichment analysis, Northern blotting, fluorescent in situ hybridization, reverse transcription polymerase chain reaction, serial analysis of gene expression, microarray, or a tiling array. 
     
     
         41 . The method of  claim 36 , wherein detecting a number of cells as fewer or greater than a control comprises single-cell RNA sequencing, affinity-based pseudotime reconstruction, flow cytometry, or immunophenotyping. 
     
     
         42 . A method of treating cancer in a subject in need thereof, the method comprising:
 (A) detecting a parameter in a peripheral blood sample from the subject, comprising detecting:
 (i) gene expression in monocytes comprising:
 (1) increased expression of TNF, FOS, JUN, JUNB, TNFAIP2, TNFAIP3, NFKB1, NFKBIA, NFKBIZ, or a combination of two or more thereof, compared to a control; 
 (2) decreased expression of IKBKB, compared to a control; 
 (3) increased expression of MYD88, compared to a control; or 
 
 (ii) a greater number of CD8+ differentiated cells, a greater number of CD4+ naive cells, fewer CD4+ differentiated cells, and fewer T follicular helper cells, compared to a control; 
 (iii) a lower density of total peripheral blood mononuclear cells, a lower density of CD4+ effector memory cells, and a higher density of classical monocytes, compared to a control; 
 (iv) gene expression in T cells comprising:
 (1) increased expression of IFIT1/3, IFITM3, IFI44L, PSME2, IFI6, ISG15, or a combination of two or more thereof, compared to a control; 
 (2) increased expression of NFKB1, MYD88, NFKBIA, NFKBIZ, or a combination of two or more thereof, compared to a control; 
 (3) increased expression of PIK3CD, PSMA7, PSMB8, PSMD9, HLA-A, HLA-B, HLA-C, HLA-DQB1, HLA-DQA1, HLA-DPB1, HLA-DPA1, HLA-DRB1, HLA-DRA, HLA-DMB, HLA-DMA, or a combination of two or more thereof, compared to a control; 
 (4) increased expression of CCL3, CCL4, CCL5, CCR5, or a combination of two or more thereof, compared to a control; 
 (5) decreased expression of CXCR3, CCR2, or a combination thereof, compared to a control; 
 (6) increased expression in CD8+ T cells in a cell death gene selected from the group consisting of CASP1, CASP3, CASP7, CASP8, and a combination of two or more thereof, compared to a control; 
 (7) a greater number of differentiated CD8+ cells, compared to a control; or 
 (8) fewer differentiated CD4+ cells compared to a control; or 
 
 (v) gene expression in monocytes comprising:
 (1) increased expression of genes upregulated by IFN stimulation, compared to a control; or 
 (2) increased expression of genes upregulated by major histocompatibility complex 2 (MCHII) production, compared to a control; and 
 
   (B) administering to the subject an effective amount of a PD-1 inhibitor.   
     
     
         43 . The method of  claim 42 , wherein the cancer is a gastrointestinal cancer. 
     
     
         44 . The method of  claim 42 , wherein the cancer is colorectal cancer, gastroesophageal cancer, pancreatic cancer, or biliary cancer. 
     
     
         45 . The method of  claim 42 , wherein the subject was previously treated with a PD-1 inhibitor. 
     
     
         46 . The method of  claim 42 , wherein detecting gene expression comprises single-cell RNA sequencing, single sample gene set enrichment analysis, Northern blotting, fluorescent in situ hybridization, reverse transcription polymerase chain reaction, serial analysis of gene expression, microarray, or a tiling array. 
     
     
         47 . The method of  claim 42 , wherein detecting a number of cells as fewer or greater than a control comprises one or more of single-cell RNA sequencing, affinity-based pseudotime reconstruction, flow cytometry or immunophenotyping. 
     
     
         48 . The method of  claim 42 , wherein the PD-1 inhibitor is pembrolizumab, nivolumab, or cemiplimab. 
     
     
         49 . A method of treating cancer in a subject in need thereof, the method comprising, in order:
 (i) administering to the subject an effective amount of a PD-1 inhibitor, and thereafter;   (ii) detecting:
 (a) an increase in peripheral blood mononuclear cells in a sample of peripheral blood from the subject, compared to a control; 
 (b) a reduced rate of tumor growth in the subject, compared to a control; or 
 (c) an increase in peripheral blood mononuclear cells in a sample of peripheral blood from the subject, compared to a control, and a reduced rate of tumor growth in the subject, compared to a control. 
   
     
     
         50 . The method of  claim 49 , further comprising administering to the subject an effective amount of a PD-1 inhibitor after step (ii). 
     
     
         51 . The method of  claim 49 , wherein the PD-1 inhibitor is pembrolizumab, nivolumab, or cemiplimab. 
     
     
         52 . The method of  claim 49 , wherein the cancer is a gastrointestinal cancer. 
     
     
         53 . The method of  claim 49 , wherein the cancer is colorectal cancer, gastroesophageal cancer, pancreatic cancer, or biliary cancer.