Check out the paper here: https://www.nature.com/articles/s41467-020-19917-0
Within the last decade, immunotherapy has revolutionized cancer treatment. However, even in the most responsive tumor types, the majority of patients fail to respond to immunotherapy alone. Preclinical studies have demonstrated that radiotherapy and immunotherapy can synergize to improve local tumor control and lead to radiation-induced antitumor immunity, or an abscopal effect1. Based on these and other promising preclinical data, there are now hundreds of clinical trials testing this treatment combination.
The vast majority of preclinical studies examining the efficacy of immune checkpoint blockade, alone or in combination with radiotherapy, have been performed using transplanted tumor models, in which cancer cells are injected subcutaneously into a naive mouse. Although studies utilizing transplanted tumors frequently demonstrate high tumor cure rates, the utility of these common transplant tumor models in the study of immunotherapy is limited because they introduce large numbers of tumor cells and can initiate artificially proinflammatory responses that are unlikely to occur during primary tumor evolution2. Primary tumor models, where a cancer develops from the tissue of origin under the pressure of the host immune system, address many limitations of transplant tumor models.
In this study, we utilize a genetically engineered mouse model of primary soft tissue sarcoma with a high mutational burden3 similar to immunotherapy-responsive human cancers4. To generate primary sarcomas, we used genetic tools to delete p53, followed by injection of the carcinogen 3-methylcholanthrene (MCA). Primary p53/MCA sarcomas develop slowly over the next 2-3 months at the site of injection in immunocompetent mice, mimicking the process of tumor development in humans.
Like many studies with tumor cell lines transplanted into syngeneic mice5,6, tumors generated by transplanting tumor cell lines generated from primary p53/MCA tumors into syngeneic mice can be completely cured by immune checkpoint blockade with radiation. However, the same combination of immune checkpoint blockade and radiation therapy fails to cure a single mouse bearing a primary p53/MCA sarcoma.
To understand the immunologic mechanisms underpinning response and resistance in tumors from the same model system, we examined the contribution of the immune system in primary tumors. We found that the adaptive immune system in primary tumors leads to immune editing and repression of transcripts encoding tumor neoantigens. Using a series of tumor transplantation experiments, we discovered that primary p53/MCA tumor development induces immune tolerance to tumor cells that coevolve with their immune system.
Next, we compared the immune profile of murine and human sarcomas. We found that the immune landscape of primary mouse sarcomas, which do not respond to immunotherapy and radiation therapy, is similar to that of most human sarcomas. In contrast, transplant sarcomas, which are cured by immunotherapy and radiation therapy, resemble only a subset of highly inflamed human sarcomas that responded to anti-PD-1 therapy7.
We comprehensively profiled tumor-infiltrating immune cells from primary and transplanted sarcomas using complementary single-cell RNA sequencing and mass cytometry, revealing striking differences in their immune landscapes. For example, radiation therapy remodels myeloid cell phenotypes in primary and transplanted sarcomas, but only transplanted tumors are enriched for the effector CD8+ T cells that mediate response to combination therapy. Our findings reveal that coevolution of tumors with the immune system generates a unique immune cell landscape that favors tumor tolerance, which is not recapitulated by transplanted tumors from the same genetically engineered model of cancer. This finding may explain why immunotherapies that show activity in transplant tumor models underperform when translated to cancer patients.
- Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).
- Crittenden, M. R. et al. Tumor cure by radiation therapy and checkpoint inhibitors depends on pre-existing immunity. Sci. Rep. 8, 7012 (2018).
- Lee, C.-L. et al. Mutational landscape in genetically engineered, carcinogen-induced, and radiation-induced mouse sarcoma. JCI Insight 4, (2019).
- Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).
- Gubin, M. M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).
- Gubin, M. M. et al. High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy. Cell 175, 1014–1030.e19 (2018).
- Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature (2020) doi:10.1038/s41586-019-1906-8.