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
... -
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DNA Damage Repair Gene Mutations Are Indicative of a Favorable Prognosis in Colorectal Cancer Treated With Immune Checkpoint Inhibitors.
DNA damage repair (DDR) genes were recently implicated in the anti-tumor immune response. Therefore, it is worthwhile to unravel the implications of DDR pathways in the shaping of immune responsiveness in colorectal cancer (CRC) patients receiving immune checkpoint inhibitors (ICI).
We analyzed publicly available genomic data from a cohort treated with ICI from Memorial Sloan Kettering Cancer Center (MSK ICI cohort). To characterize the impact of the DDR mutation, the genomic data of The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma (COADREAD) dataset was explored. We also analyzed the incidence of DDR mutation and microsatellite instability-high (MSI-H) in a Chinese CRC cohort using panel sequencing.
The DDR pathway was commonly mutated (21.8%) in the multicancer MSK ICI cohort, with the highest frequency of 36.4% in CRCs. Survival analysis showed that DDR mutation correlated with an improved overall survival (OS) in CRCs and pan-cancer in the MSK ICI cohort. However, no significant associations were identified in the TCGA COADREAD and MSK non-ICI CRCs. DDR mutation was associated with higher tumor mutational burden (TMB) levels and increased immune cell infiltration and immune checkpoint molecule expression in the TCGA COADREAD dataset. Last, we investigated the DDR mutational pattern and its associations with MSI-H and other genomic features in a Chinese CRC cohort. Notably, MSI-H and DDR mutation was present in 5.7% and 13.4% of cases, respectively, which suggests that DDR identifies a higher proportion of potential responders than MSI-H.
Our data suggest that DDR mutation as an indication of enhanced cancer immunity, and it may function as a biomarker for patients with CRCs receiving ICI treatment. The high incidence of DDR mutation in the Chinese CRC cohort emphasizes the future utility of panel-based DDR evaluation in guiding ICI treatment.
Song Y
，Huang J
，Liang D
，Hu Y
，Mao B
，Li Q
，Sun H
，Yang Y
，Zhang J
，Zhang H
，Chen H
，Liu H
，Zhang S
... -
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Homologous recombination repair gene mutations in colorectal cancer favors treatment of immune checkpoint inhibitors.
Immune checkpoint inhibitor (ICI) therapy is insensitive for Colorectal cancer (CRC) patients with microsatellite stable (MSS). Genomic data of three CRC cohort, n = 35), and the Cancer Genome Atlas (TCGA CRC cohort, n = 377), were analyzed. A cohort treated with ICIs from Memorial Sloan Kettering Cancer Center (MSKCC CRC cohort, n = 110) and two cases from the local hospital were characterized the impact of the HRR mutation on prognosis of CRC. Homologous recombination repair (HRR) gene mutations were more common in CN and HL cohorts (27.85%; 48.57%) than in TCGA CRC cohort (15.92%), especially in the MSS populations, the frequencies of HRR mutation were higher in CN and HL cohort (27.45%, 51.72%) than in TCGA cohort (6.85%). HRR mutations were associated with high tumor mutational burden (TMB-H). Although HRR mutation uncorrelated with an improved overall survival in the MSKCC CRC cohort (p = 0.97), HRR mutated patients had a significantly improved OS compared to the HRR wildtype population particularly in MSS subgroups (p = 0.0407) under ICI treatment. It probably contributed by a higher neoantigen and increased CD4+ T cell infiltration which found in the TCGA MSS HRR mutated CRC cohort. The similar phenomenon on cases was observed that MSS metastatic CRC patient with HRR mutation seemed more sensitive to ICI after multi-line chemotherapy in clinical practice than HRR wildtype. This finding suggests the feasibility of HRR mutation as an immunotherapy response predictor in MSS CRC, which highlights a potential therapeutic approach for these patients.
Lin Y
，Luo S
，Luo M
，Lu X
，Li Q
，Xie M
，Huang Y
，Liao X
，Zhang Y
，Li Y
，Liang R
... -
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ResearchGate
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钛学术
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