Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth

Abstract

Molecular alterations in genes involved in DNA mismatch repair (MMR) promote cancer initiation and foster tumour progression. Cancers deficient in MMR frequently show favourable prognosis and indolent progression. The functional basis of the clinical outcome of patients with tumours that are deficient in MMR is not clear. Here we genetically inactivate MutL homologue 1 (MLH1) in colorectal, breast and pancreatic mouse cancer cells. The growth of MMR-deficient cells was comparable to their proficient counterparts in vitro and on transplantation in immunocompromised mice. By contrast, MMR-deficient cancer cells grew poorly when transplanted in syngeneic mice. The inactivation of MMR increased the mutational burden and led to dynamic mutational profiles, which resulted in the persistent renewal of neoantigens in vitro and in vivo, whereas MMR-proficient cells exhibited stable mutational load and neoantigen profiles over time. Immune surveillance improved when cancer cells, in which MLH1 had been inactivated, accumulated neoantigens for several generations. When restricted to a clonal population, the dynamic generation of neoantigens driven by MMR further increased immune surveillance. Inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models. These results suggest that targeting DNA repair processes can increase the burden of neoantigens in tumour cells; this has the potential to be exploited in therapeutic approaches.

Comparison of a combination of chemotherapy and immune checkpoint inhibitors and immune checkpoint inhibitors alone for the treatment of advanced and metastatic non‐small cell lung cancer

“…A number of combined treatment approaches with ICIs have been proposed to deal with the issue of resistance . Among these, the combination of chemotherapy, the standard of care for advanced NSCLC patients, is one of the most widely used strategies as it is also likely to address the multifaceted mechanisms of tumor immune escape.…”

“…Among these, the combination of chemotherapy, the standard of care for advanced NSCLC patients, is one of the most widely used strategies as it is also likely to address the multifaceted mechanisms of tumor immune escape. Earlier studies have shown that chemotherapy can boost tumor immunogenicity for immune recognition by inducing immunogenic cell death and the release of neoantigens . Chemotherapy also enhances antigen presentation as a result of the increased expression of MHC class I molecules in murine models, thereby boosting the recruitment and proliferation of tumor‐specific effector T cells .…”

BAP1 Loss Predicts Therapeutic Vulnerability in Malignant Peritoneal Mesothelioma

“…More recent studies in ccRCC [36] and melanoma [37] demonstrated that inactivation of PBRM1 (or PBAF complex) predicts response to immune checkpoint blocking therapies. Similarly, DNA repair defects have also been shown to be predictive of response to immune checkpoint blocking therapies [38][39][40]. This strongly indicates a pan-cancer mechanism of oncogenesis shared among tumors with BAP1 copy-number loss.…”

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

“…Several other predictive markers of genomic profiles other than MSI testing have been evaluated, such as PD-L1 expression, prediction of neo-epitopes or tumor mutational burden, but for PDAC none of these approaches has so far been clinically relevant [104,105]. Whether or not genomic signatures predicting a ‘BRCA-ness' phenotype might also predict enhanced sensitivity to therapeutic immune checkpoint inhibition remains a matter of ongoing research, so far [83,105].…”

“…Several other predictive markers of genomic profiles other than MSI testing have been evaluated, such as PD-L1 expression, prediction of neo-epitopes or tumor mutational burden, but for PDAC none of these approaches has so far been clinically relevant [104,105]. Whether or not genomic signatures predicting a ‘BRCA-ness' phenotype might also predict enhanced sensitivity to therapeutic immune checkpoint inhibition remains a matter of ongoing research, so far [83,105]. On the other hand, combination partners are evaluated for their potential to sensitize tumors to immune checkpoint inhibitor therapy; thus, many of the traditional cytotoxic agents commonly used in pancreatic cancer therapy, such as gemcitabine, 5-fluorouracil (5-FU) or oxaliplatin, have long been known to also confer immunomodulatory efficacy and are therefore candidates for combinatorial regimens to improve the response rates observed in current immunotherapeutic schemes [106,107,108,109].…”