Age, sex, and specific gene mutations affect the effects of immune checkpoint inhibitors in colorectal cancer.

The effect of age and sex on the predictive value of colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs) has been controversial, and the effect of specific gene mutations on the predictive value of CRC patients treated with ICIs remains to be explored. Our study analyzed the influence of the above factors on the overall survival (OS) of CRC patients receiving ICIs and explored the influencing mechanism of various predictive biomakers. We performed survival prognostic correlation analysis and bioinformatics analysis on the clinical CRC cohort receiving ICIs in from the Memorial Sloan Kettering Cancer Center (MSKCC) and the clinical and genetic data from The Cancer Genome Atlas (TCGA)-CRC dataset, including immunogenicity analysis, tumor immune microenvironment analysis, and gene set enrichment analysis and so on. We found that mutation count >11 mutation/Mb (tumor mutation burden, TMB-high) (HR = 0.22, 95 %CI: 0.09-0.53; P < 0.001), male (HR = 0.51, 95 %CI: 0.28-0.93; P = 0.029), RNF43-mutant (MT) (HR = 0.12, 95 %CI: 0.03-0.49; P = 0.003), CREBBP-MT (HR = 0.23, 95 %CI: 0.07-0.76; P = 0.016), NOTCH3-MT (HR = 0.17, 95 %CI: 0.04-0.74; P = 0018), PTCH1-MT (HR = 0.27, 95 %CI: 0.08-0.9; P = 0.033), CIC-MT (HR = 0.23, 95 %CI: 0.05-0.93; P = 0.040), DNMT1-MT (HR = 0.12, 95 %CI: 0.02-0.93; P = 0.043) and SPEN-MT (HR = 0.31, 95 %CI: 0.09-0.99; P < 0.049) are all related to longer OS, but age≤65 years (HR = 3.01, 95 %CI: 1.18-7.65; P = 0.021), APC-MT (HR = 2.51, 95 %CI: 1.12-5.63; P = 0.026) and TP53-MT (HR = 1.94, 95 %CI: 1.03-3.65; P = 0.041) are associated with shorter OS. The reason why positive predictive markers provide survival benefits to CRC may be related to higher immunogenicity such as TMB, highly expression of mRNA related to immune response, highly infiltrating immune-active cells such as CD8 + T cells, active immune-active pathways, and DNA damage repair pathways with an increased number of mutations.

Lin A ，Zhang H ，Hu X ，Chen X ，Wu G ，Luo P ，Zhang J ... -  《-》

Analysis of Interleukin-1 Signaling Alterations of Colon Adenocarcinoma Identified Implications for Immunotherapy.

Immune checkpoint inhibitors (ICIs) have made breakthrough progress in the treatment of various malignant tumors. However, only some patients receiving ICIs obtain long-lasting clinical effects, and some patients still do not achieve remission. Improving the treatment benefits of this part of the population has become a concern of clinicians. IL-1 signaling plays an important role in the tumor microenvironment (TME). However, the relationship between the IL-1 signaling mutation status and the prognosis of colon adenocarcinoma (COAD) patients receiving ICIs has not been reported. We downloaded the data of a COAD cohort receiving ICIs, including prognostic data and mutation data. Additionally, we downloaded the data of a COAD cohort from The Cancer Genome Atlas (TCGA) database, including clinical data, expression data and mutation data. Gene set enrichment analysis (GSEA) was used to assess differences in the activity of some key physiological pathways between the IL-1 signaling mutated-type (IL-1-MT) and IL-1 signaling wild-type (IL-1-WT) groups. The CIBERSORT algorithm was used to evaluate the contents of immune cells in the TME of COAD patients. The multivariate Cox regression model results suggested that IL-1-MT can be used as an independent predictor of a better prognosis in COAD patients receiving ICIs (P = 0.03, HR = 0.269, 95% CI: 0.082-0.883). Additionally, IL-1-MT COAD patients had significantly longer overall survival (OS) (log-rank P = 0.015). CIBERSORT analysis showed that the IL-1-MT group had high infiltration levels of activated dendritic cells (DCs), M1 macrophages, neutrophils, activated natural killer (NK) cells, activated CD4+ memory T cells and CD8+ T cells. Similarly, the IL-1-MT group had significantly upregulated immunogenicity, including in terms of the tumor mutation burden (TMB), neoantigen load (NAL) and number of mutations in DNA damage repair (DDR) signaling. GSEA showed that the IL-1-MT group was highly enriched in the immune response and proinflammatory mediators. Additionally, the expression levels of immune-related genes, immune checkpoint molecules and immune-related signatures were significantly higher in the IL-1-MT group than in the IL-1-WT group. IL-1-MT may be an independent predictor of a good prognosis in COAD patients receiving ICIs, with significantly longer OS in IL-1-MT COAD patients. Additionally, IL-1-MT was associated with significantly increased immunogenicity, activated immune cell and inflammatory mediator levels and immune response-related scores.

Zhou X ，Liu Y ，Xiang J ，Wang Y ，Wang Q ，Xia J ，Chen Y ，Bai Y ... -  《Frontiers in Immunology》

Tumor Mutational Burden Predicting the Efficacy of Immune Checkpoint Inhibitors in Colorectal Cancer: A Systematic Review and Meta-Analysis.

For colorectal cancer patients, traditional biomarker deficient mismatch repair/microsatellite instability (dMMR/MSI) is an accurate predictor of immune checkpoint inhibitors (ICIs). Recent years, researchers considered tumor mutation burden (TMB) as another predictive biomarker which means the number of nonsynonymous mutations in cancer cells. Several studies have proven that TMB can evaluate the efficacy of ICI therapy in diverse types of cancer, especially in non-small cell lung cancer and melanoma. However, studies on the association between TMB and the response to ICI therapy in colorectal cancer alone are still lacking. In this study, we aim to verify the effect of TMB as a biomarker in predicting the efficacy of ICIs in colorectal cancer. We searched the PubMed and Ovid MEDLINE databases up to May 1, 2021 and screened studies for eligibility. Thirteen studies published from 2015 to 2021 with 5062 patients were included finally. We extracted and calculated hazard ratios (HRs) and odds ratios (ORs) of overall survival (OS) and objective response rates (ORRs) and their 95% confidence intervals (95% CIs). Pooled HR and OR were evaluated to compare OS and ORR between TMB-high and TMB-low groups in colorectal cancer patients. Meanwhile, we assessed heterogeneity with the I2 statistic and p-values and performed publication bias assessments, sensitivity analyses, and subgroup analyses to search the cause of heterogeneity. The TMB-high patient group had a longer OS than the TMB-low patient group (HR = 0.68, 95% CI: 0.51, 0.92, p = 0.013) among colorectal cancer patients receiving ICIs. In addition, the TMB-high patient group was superior in terms of ORR (OR = 19.25, 95% CI: 10.06, 36.82, p < 0.001) compared to the TMB-low patient group. In conclusion, this meta-analysis revealed that TMB can be used as a potential predictive biomarker of colorectal cancer patients receiving ICI therapy. Nevertheless, this finding is not stable enough. Therefore, many more randomized controlled trials are needed to prove that TMB is reliable enough to be used clinically to predict the efficacy of immunotherapy in colorectal cancer. And the most relevant biomarker remains to be determined when TMB high overlaps with other biomarkers like MSI and TILs.

Li Y ，Ma Y ，Wu Z ，Zeng F ，Song B ，Zhang Y ，Li J ，Lui S ，Wu M ... -  《Frontiers in Immunology》

Alterations in TP53 Are a Potential Biomarker of Bladder Cancer Patients Who Benefit From Immune Checkpoint Inhibition.

Lyu Q ，Lin A ，Cao M ，Xu A ，Luo P ，Zhang J ... -  《-》

The Role of SPEN Mutations as Predictive Biomarkers for Immunotherapy Response in Colorectal Cancer: Insights from a Retrospective Cohort Analysis.

Dong Y ，Ye S ，Li H ，Li J ，Liu R ，Zhu Y ... -  《-》