High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors

Abstract

Tumors responding to immune checkpoint inhibitors (ICIs) have a higher level of immune infiltrates and/or an Interferon (IFN) signature indicative of a T-cell-inflamed phenotype. Melanoma and lung cancer demonstrate high response rates to ICIs and are commonly referred to as "hot tumors". These are in sharp contrast to tumors with low immune infiltrates called "cold tumors" or non-T-cell-inflamed cancers, such as those from the prostate and pancreas. Classification of tumors based on their immune phenotype can partially explain clinical response to ICIs. However, this model alone cannot fully explain the lack of response among many patients treated with ICIs.Dichotomizing tumors based on their mutation profile into high tumor mutation burden (TMB) or low TMB, such as many childhood malignancies, can also, to some extent, explain the clinical response to immunotherapy. This model mainly focuses on a tumor's genotype rather than its immune phenotype. High TMB tumors often have higher levels of neoantigens that can be recognized by the immune system. In the current era of immunotherapy, with the lack of definitive biomarkers, we need to evaluate tumors based on both their immune phenotype and genomic mutation profile to determine which patients have a higher likelihood of responding to treatment with ICIs.

Keywords: Cancer; Checkpoint inhibitors; High TMB and low TMB tumors; Hot and cold tumors; Immunotherapy; T-cell-inflamed and non-T-cell-inflamed tumors.

Fig. 1

Schematic diagram of high TMB and low TMB tumors versus hot and cold tumor types and their likelihood of response to ICIs. Tumors with higher somatic mutation prevalence such as melanoma and NSCLC are among high TMB tumors (highly mutated). However, some high TMB tumors can be either hot (T-cell-inflamed) or cold (non-T-cell-inflamed) based on their T-cell and IFN signature (immune phenotype). MMR-deficient CCR cancers are both high TMB and immunologically hot, while MSS CCRs have relatively high mutation rate, but non-T-cell-inflamed. HPV⁺ HNSCC are similar to HPV⁻ HNSCC in their mutation burden, but are more T-cell-inflamed. MCC, ovarian cancer, and RCC have modest mutation rates with a relatively T-cell-inflamed phenotype. Neuroblastoma, prostate, and pancreatic cancers are both immunologically cold and have relatively low mutation burden