Table 1.
Germline Immune Genetic Associations with Immunotherapy Outcomes
| Ref | Cancer | Treatment | Outcome | # subjects | Immune Genes | Immune gene function* | Main germline immune genetic associations found | Statistical significance of association |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| (44) | Bladder | BCG vaccine | Recurrence | 125 | TNFA, IL2RA, IL17A, IL17RA, IL18R1, ICAM-1, FASL, TRAILR1 | Cytokines – TNF family and Interleukins; Antimicrobial (regulates cell death); antigen processing and presentation | Patients with SNPs in immune and inflammatory genes had increased risk of recurrence after treatment. | HR values ranged between 1.70 and 5.19 |
| (33) | Bladder | Anti-PD-L1 (atezolizumab) | OS | 311 | TWAS identified variants associated with ERAP2 | Antigen processing and presentation | Lower ERAP2 expression levels were associated with improved response to atezolizumab (better OS) in luminal subtype bladder cancer patients. | p=0.03 |
| (42) | Ovarian | Farletuzumab (anti-folate receptor α) | PFS | 461 | FCGR2A, FCGR3A | Antigen-antibody - Immunoglobulin receptor on macrophages, neutrophils, Natural Killer cell | Enhanced clinical outcome was observed in patients with at least one high affinity allele of FCGR2A and FCGR3A (FCGR2A-131H and FCGR3A-158V alleles), with CA125<3xULN and received optimal farletuzumab. | HR=0.25, p=0.0202 |
| (43) | Renal cell carcinoma | High-dose aldesleukin (HD-IL2) | Tumor shrinkage | 106 | FCGR2A, FCGR3A, FCGR2C | Antigen-antibody - Immunoglobulin receptor on macrophages, neutrophils, Natural Killer cell | Higher affinity genotypes for FCGR2A, FCGR3A, FCGR2C together (i.e. favorable FCGR genotype group) were associated with increased tumor shrinkage. | p=0.03 |
| (46) | Melanoma | TAPcell vaccine | OS | 53 | TLR4 | Antimicrobial – Pathogen recognition and activation of innate immunity | Excluding patients with short post therapy response, patients bearing TLR4 896G allele had a significantly lower post therapy median survival than those with the normal allele (12 vs. 29 months). | p=0.026 |
| (35) | Melanoma | Anti-CTLA4 (ipilimumab, tremelimumab), anti-PD1 (nivolumab, pembrolizumab), or combined anti-CTLA4/anti-PD1 (ipilimumab/nivolumab) | Response to treatment | 436 | IL2, IL21 locus | Cytokine - Interleukin | rs17388568 (in IL2, IL21 locus) was associated with increased anti-PD1 response. | OR=0.26 (0.12–0.53), p=0.0002 |
| (58) | AML | Histamine dihydrochloride and low dose IL-2 immunotherapy | Leukemia free survival (LFS) and OS | 84 | HLA-B | Antigen processing and presentation | HLA-B-21M patients had improved LFS and OS compared to HLA-B-21T patients. | LFS (p=0.04; p=0.02); OS (p=0.007; p=0.003) |
| (59) | Melanoma and NSCLC | Anti–CTLA-4 or anti–PD-1 therapy | OS | 269 melanoma; 100 NSCLC | HLA-B44 | Antigen processing and presentation | Patients with B44 superfamily alleles had significantly better survival. | HR=0.61 (0.42–0.89), p=0.01 |
| (60) | Melanoma | Interferon | RFS | 286 | HLA genotypes | Antigen processing and presentation | HLA-Cw 06-positive patients had better RFS. | p=0.013 |
| (40) | Melanoma | Adoptive therapy (TILs) | Response to treatment | 140 | IRF5 genotype | Antimicrobial – virus mediated activation of interferon and modulation of cell growth | Lack of A allele in IRF5 genotype (rs10954213 G > A) was associated with non-response to TIL therapy. | p<0.005 |
| (49) | Melanoma | Adoptive therapy (TILs) | Response to treatment | 142 | CXCR3 and CCR5 genotypes | Cytokine – chemokine receptor | CXCR3 genotype and CCR5Δ32 deletion were associated with gene under expression and response to treatment. | OR=6.16 (complete response) and 2.32 (for overall response) |
| (61) | Melanoma | CTLA-4 blockade (ipilimumab or tremelimumab) | OS | 14 | Six CTLA4 polymorphisms (SNPs −1661A>G, −1577G>A, −658C>T, −319C>T, +49A>G, and CT60G>A) | T cell receptor signaling pathway | CTLA4−1577G/A and CT60G/A genotypes were significantly associated with improved overall survival. | p<0.006 |
*
Immune gene function: The immune system role of the protein encoded by the gene identified as being associated with cancer treatment outcome is indicated. The category designation was made as per Immport.org/shared/genelists and/or Genecards.org. Note that Cytokines can have various functions in mediating the immune system (such as inflammation, response to infection, etc.) through cell signaling; please refer to Genecards.org for a more comprehensive discussion of the gene functions.