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DNA mismatch repair in cancer immunotherapy.

ABSTRACT: Tumors defective in DNA mismatch repair (dMMR) exhibit microsatellite instability (MSI). Currently, patients with dMMR tumors are benefitted from anti-PD-1/PDL1-based immune checkpoint inhibitor (ICI) therapy. Over the past several years, great progress has been made in understanding the mechanisms by which dMMR tumors respond to ICI, including the identification of mutator phenotype-generated neoantigens, cytosolic DNA-mediated activation of the cGAS-STING pathway, type-I interferon signaling and high tumor-infiltration of lymphocytes in dMMR tumors. Although ICI therapy shows great clinical benefits, ∼50% of dMMR tumors are eventually not responsive. Here we review the discovery, development and molecular basis of dMMR-mediated immunotherapy, as well as tumor resistant problems and potential therapeutic interventions to overcome the resistance.

SUBMITTER: Guan J

PROVIDER: S-EPMC10262306 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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DNA mismatch repair in cancer immunotherapy.

Guan Junhong J Li Guo-Min GM

NAR cancer 20230613 3

Tumors defective in DNA mismatch repair (dMMR) exhibit microsatellite instability (MSI). Currently, patients with dMMR tumors are benefitted from anti-PD-1/PDL1-based immune checkpoint inhibitor (ICI) therapy. Over the past several years, great progress has been made in understanding the mechanisms by which dMMR tumors respond to ICI, including the identification of mutator phenotype-generated neoantigens, cytosolic DNA-mediated activation of the cGAS-STING pathway, type-I interferon signaling a ...[more]

PMID: 37325548

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Project description:BackgroundNeoadjuvant immunotherapy (NIT) has been endorsed by clinical guidelines for the management of DNA mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H) locally advanced rectal cancer (LARC). Nonetheless, the therapeutic efficacy of NIT in mismatch repair-proficient/microsatellite stable (pMMR/MSS) non-metastatic rectal cancer (RC) remain pending matters. Therefore, a meta-analysis was carried out to assess the efficacy and safety of NIT in patients with non-metastatic pMMR/MSS RC.MethodsPubMed, Embase, Web of Science, the Cochrane Library, ClinicalTrials.gov, ASCO and ESMO were searched to obtain related studies up to July 2024. Two reviewers independently screened the included articles and extracted the pertinent data. The risk of publication bias was assessed by Begg or Egger tests and in cases of publication bias, the trim and fill method was applied. Heterogeneity was assessed using I 2 statistics.ResultsThirteen articles including 582 eligible patients were analyzed. The pooled pCR, MPR, cCR and anus preservation rate were 37%, 57%, 26% and 77% separately and the incidence of irAEs≥3 grades and TRAEs≥3 grades were 3% and 29%, respectively. Non-metastatic pMMR/MSS RC receiving the short-course radiotherapy (SCRT) in neoadjuvant setting exhibited superior pooled pCR and MPR than long-course radiotherapy (LCRT) without upregulating the incidence of adverse effects. Furthermore, patients with MSS RC underwent neoadjuvant treatment with anti-PD-1 inhibitors demonstrated higher pooled pCR, MPR, cCR compared to those receiving PD-L1 inhibitors. Additionally, yielded improved pooled MPR and anal preservation rates compared to sequential immuno-radiotherapy (63.4% vs 51.2% and 88.5% vs 69.9%), without raising the incidence of irAEs≥3 grade. Interestingly, RC patients with lymph node metastasis showed a higher pooled pCR than those without lymph node metastasis (43% vs 35%).ConclusionNIT was linked to favorable response rates and anal preservation, alongside an acceptable safety profile. Non-metastatic pMMR/MSS RC patients receiving SCRT, PD-1 inhibitors, or concurrent immuno-radiotherapy in the neoadjuvant setting exhibited enhanced outcomes. This meta-analysis provides evidence for further exploration and application of NIT in non-metastatic pMMR/MSS RC and highlights the potential for organ preservation with this approach. The relatively small sample size and the uneven quality of included studies may have had some impact on the generality of the results. Therefore, further analysis with a higher number of high-quality studies is needed to verify the conclusions.Systematic review registrationhttps://inplasy.com/, identifier: INPLASY202470110.

Project description:BackgroundGenomic biomarkers that predict response to anti-PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti-PD1 therapy in prostate cancer.MethodsTo enrich for response to anti-PD1 therapy, we assembled a multicenter cohort of 65 men with mismatch repair-deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden, and frameshift mutation proportion (FSP), which were correlated to outcomes on anti-PD1 treatment. We subsequently used data from a clinical trial of pembrolizumab in patients with nonprostatic dMMR cancers of various histologies as a biomarker validation cohort.ResultsNineteen of 65 patients with dMMR metastatic castration-resistant prostate cancer were treated with anti-PD1 therapy. The PSA50 response rate was 65%, and the median progression-free survival (PFS) was 24 (95% confidence interval 16-54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti-PD1 treatment and with density of CD8+ tumor-infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti-PD1 therapy in a validation cohort.ConclusionTumor FSP correlated with prolonged efficacy of anti-PD1 treatment among patients with dMMR cancers and may represent a new biomarker of immune checkpoint inhibitor sensitivity.Implications for practiceGiven the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, a cohort of patients with DNA mismatch repair-deficient (dMMR) prostate cancer was assembled, as these patients are enriched for responses to ICI. A high response rate to anti-PD1 therapy in these patients was observed; however, these responses were not durable in most patients. Notably, tumor frameshift mutation proportion (FSP) was identified as a novel biomarker that was associated with prolonged response to anti-PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti-PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts.

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DNA mismatch repair in cancer immunotherapy.

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DNA mismatch repair in cancer immunotherapy.

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