Evolutionary trajectories of tumors following resistance to immune checkpoint blockade

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PROJECT SUMMARY Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but the majority of patients who receive ICB develop resistance and ultimately need to be treated with multiple therapies. Mapping the expected patterns of evolution has enabled rational sequencing of treatments for many cancer therapies, particularly targeted therapies. However, we currently have a limited understanding of how treatment with ICB shapes the evolutionary trajectory of a tumor. Most cancer therapies kill tumor cells directly and leave behind a small remnant of cell-intrinsically drug-resistant tumor cells; from an evolutionary perspective, this results in a clonal sweep after treatment in which drug-resistant cells take over the tumor. In contrast, ICB acts by mobilizing a patient’s own immune cells, particularly T cells, against the tumor, and tumors frequently develop resistance to ICB by establishing a “cold” tumor microenvironment that is inhospitable to T cells. In cases where ICB resistance is mediated by the entire tumor microenvironment, it is not clear that resistance will be accompanied by such a clonal sweep; rather, it raises the question as to whether tumor cells which would be sensitive to ICB on their own might be protected if they reside alongside neighbors that can create a sufficiently “cold” microenvironment. In support of this, a study of melanoma patients has suggested that an evolutionary pattern of clonal persistence—in which many tumor populations survive therapy—is found in many ICB- resistant tumors. In this proposal, we will seek to map out the evolutionary trajectories of tumors after ICB in both a mouse model of squamous cell carcinoma and in bladder cancer patients. We will in particular seek to test the hypothesis that clonal persistence is dominant pattern of evolution following ICB, particularly in tumors which exhibit a “cold” microenvironment. We have established a novel mouse model system in which we can track multiple tumor populations in the same tumor—e.g., an “immune hot” and an “immune cold” population— via fluorescent tags. We will use this model to interrogate whether the presence of an “immune cold” tumor population that drives a “cold” microenvironment can protect otherwise-sensitive “immune hot” tumor cells from ICB-mediated clearance. Such protection by a “cold” tumor population would establish a mechanistic link between a “cold” microenvironment and an evolutionary pattern of clonal persistence. We will complement these studies with genomic analysis of tumors that have been treated with ICB, investigating both mouse squamous skin carcinomas treated with a-PD-1/a-TGFb combination therapy and patient bladder tumors treated with a-PD-L1. By constructing a detailed picture of pre- and post-ICB tumor clonal architecture across these two cohorts, we will map the evolutionary trajectories of ICB-treated tumors and determine whether a pattern of clonal persistence is associated with ICB resistance and specifically with a “cold” tumor microenvironment.