Abstract Cancer is an evolutionary process shaped by selective pressure from the microenvironments. However, recent studies reveal that certain tumors undergo neutral evolution where there is no detectable fitness difference amongst the cells following malignant transformation. Here, through computational modeling, we demonstrate that negative frequency-dependent selection (or NFDS), where the immune response against cancer cells depends on the clonality of neoantigens, can lead to an immunogenic landscape that is highly similar to neutral evolution. Crucially, NFDS promotes high antigenic heterogeneity and early immune evasion in hypermutable tumors, leading to poor responses to immune checkpoint blockade (ICB) therapy. Our model also reveals that NFDS is characterized by a negative association between average clonality and total burden of neoantigens. Indeed, this unique feature of NFDS is common in the whole-exome sequencing (WES) datasets (357 tumor samples from 275 patients) from four melanoma cohorts with ICB therapy and a non-small cell lung cancer (NSCLC) WES dataset (327 tumor samples from 100 patients). Altogether, our study provides quantitative evidence supporting the theory of NFDS in cancer, explaining the high prevalence of neutral-looking tumors. These findings also highlight the critical role of frequency-dependent selection in devising more efficient and predictive immunotherapies. 

pdf/frequency-dependent-selection-of-neoantigens-fosters-tumor-upc4a7nfb9.pdf

Frequency-dependent selection of neoantigens fosters tumor immune escape and predicts immunotherapy response

Abstract Cancer progression is an evolutionary process undergoing stringent immune selection. However, recent studies have revealed that certain tumors undergo neutral evolution following the malignant transformation. Here, we propose negative frequency-dependent selection (or NFDS), where the immune response against cancer cells depends on the clonality of neoantigens, can lead to an immunogenic landscape that is similar to neutral evolution. With a stochastic model of NFDS, we demonstrated that NFDSpromotes early immune evasion in hypermutable tumors, leading to neutral-like evolutionary dynamics with high antigenic heterogeneity and worse response to immune checkpoint blockade (ICB) therapy. Our model also revealed that NFDSis characterized by a negative association between average clonality and total burden of neoantigens. Indeed, NFDS was validated with whole-exome sequencing datasets (357 tumor samples from 275 patients) from four melanoma cohorts with ICB therapy. Altogether, our study provides the first quantitative evidence supporting the theory of NFDS in immune-driven cancer evolution. These findings highlight the critical role of NFDS theory in devising more efficient and predictive immunotherapies. 

Background Cancer has become an important cause of death in solid organ transplant patients. The cause of malignancies in patients with solid organ transplants is multifactorial, but the use of intensive immunosuppression is regarded as an important factor. We describe the spontaneous, complete regression of colon cancer liver metastases, without initiation of antitumor therapy, in a solid organ transplant patient after modulation of immunosuppressants. Case Presentation. A 59-year-old female was admitted with fever, general discomfort, and elevated liver enzymes. She had received a single lung transplant, five years prior, for end-stage chronic obstructive pulmonary disease. Abdominal ultrasound and a computed tomography scan showed extensive liver lesions, and liver biopsy determined that the lesions were liver metastases originating from a colonic adenocarcinoma. Histopathologic analysis revealed that the primary tumor and liver metastases were mismatch repair-deficient (BRAFV600E mutant and MLH1/PMS2-deficient), also known as a microsatellite instable tumor. The patient's clinical condition deteriorated rapidly, and she was discharged home with palliative care. No antitumor treatment was initiated. Additionally, there was a short period without any immunosuppressants. Unexpectedly, her clinical condition improved, and complete regression of liver metastases was observed on imaging two months later. Unfortunately, the patient developed rejection of her lung transplant and succumbed to pulmonary disease six months following her cancer diagnosis. The autopsy confirmed the primary colon tumor location and complete regression of >40 liver metastases. Conclusions Disinhibition and reset of the host immune response could have led to immune destruction of the liver metastases of this patient's immunogenic dMMR colon carcinoma. This case underscores the huge impact that temporary relief from immunosuppressive therapy could have on tumor homeostasis. Balanced management of care for organ transplant recipients with malignancies requires a multidisciplinary approach involving medical oncologists and transplant physicians to reach the best quality of care in these complex cases.

/pdf/spontaneous-complete-regression-of-colon-cancer-liver-1lw5p1vx.pdf

Spontaneous Complete Regression of Colon Cancer Liver Metastases in a Lung Transplant Patient: A Case Report

Mutation rate optimisation drives evolution and immune evasion of bacteria and lentiviral strains, including HIV. Whether evolving cancer lineages similarly adapt mutation rates to increase tumour cell fitness is unknown. Here, by mapping the clonal topography of mismatch repair-deficient (MMRd) colorectal cancer, we show that genomic MMRd mutability co-evolves with neoantigen selection to drive intratumour diversification and immune escape. Mechanistically, we find that microsatellite instability modulates subclonal DNA repair by toggling two hypermutable mononucleotide homopolymer runs in the mismatch repair genes MSH6 and MSH3 (C8 and A8, respectively) through stochastic frameshift switching. Spontaneous mutation and reversion at these evolvability switches modulates subclonal mutation rate, mutation bias, and clonal HLA diversity during MMRd cancer evolution. Combined experimental and simulation studies demonstrate that subclonal immune selection favours incremental MMR mutations. MMRd cancers thus fuel intratumour heterogeneity by adapting subclonal mutation rate and mutation bias to immune selection, revealing a conserved co-evolutionary arms race between neoantigen selection and adaptive genomic mutability. Our work reveals layers of mutational complexity and microsatellite biology in MMRd cancer evolution previously hidden in bulk analyses.

Mutation Rate Evolution Drives Immune Escape In Mismatch Repair-Deficient Cancer

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Mutation Rate Evolution Drives Immune Escape In Mismatch Repair-Deficient Cancer