Systemic dysfunction and plasticity of the immune macroenvironment in cancer models

Immunotherapy has provided new opportunities for the treatment of cancer patients. However, a more comprehensive understanding of immune responses in cancer and its progression is needed to increase its effectiveness for all patients. Although intratumoral CD8 T cells have been the primary focus of cancer immunotherapies, several studies shed light on the importance of a widespread anti-tumor immune response in effective immunotherapy. Despite this, a complete understanding of how cancer development impacts the overall immune condition has yet to be fully defined.

Drs. Breanna Allen and Kamir Hiam-Galvez et al. published a paper in Nature Medicine in May 2020 which defined the systemic immune landscape in response to developing tumors across five tissues (blood, spleen, bone marrow, tumor draining lymph node, and tumor) in eight different mouse tumor models. Using a 41-marker pan-immune CyTOF panel to profile the abundance and activity state of immune cell subsets, the authors described changes in immune cell frequencies and cell states across immune organs over time that tracked with tumor growth. Interestingly, some models showed higher levels of tumor-associated macrophages, while others had a high abundance of eosinophils, among other features.

Defined the systemic immune landscape across five immune organs in eight different mouse tumor models

In addition, the authors assessed the ability of these mice to mount anti-viral or -bacterial responses to a microbial challenge in the presence of a tumor, given the changes observed in the peripheral immune system in response to tumor growth. Tumor-bearing mice after infection showed impaired proliferation, differentiation, and expression of granzyme B in CD8+ T cells. Furthermore, the authors also found lower levels of expression of co-stimulatory molecules CD80 and CD86 and the activation marker CD83 in dendritic cells compared to tumor-free controls. Treatment of the tumor-burden mice with an anti-CD40 antibody increased the expression level of CD80, CD54, and PD-L1 on DCs and rescued CD8+ T cell proliferation towards levels observed in controls, highlighting the potential impaired role of APCs to drive T cell responses due to tumor burden. The authors also showed that surgical resection of tumors in murine tumor models reversed the systemic immune changes accompanied by tumor progression.

Treatment of the tumor-burden mice with an anti-CD40 antibody increased the expression level of CD80, CD54, and PD-L1 on DCs and rescued CD8+ T cell proliferation

Although tumor-burdened mice were able to withstand and clear the infection by microbial challenge, these changes to the immune system, both innate and adaptive, may be connected to cancer patients’ increased susceptibility to infection during the course of their disease and treatment. Regarding treatment, neoadjuvant versus adjuvant therapy and its benefits in different solid tumors are still highly debated. The fact that the growth and removal of tumors in this murine model shows significant changes in T cells, APCs, and other peripheral immune cells sheds light on the possibility that certain immuno-modulatory therapies may be more or less effective depending on the presence or absence of tumors.

Reference Citation: Allen BM, Hiam KJ, Burnett CE, Venida A, DeBarge R, Tenvooren I, Marquez DM, Cho NW, Carmi Y, Spitzer MH. Systemic dysfunction and plasticity of the immune macroenvironment in cancer models. Nat Med. 2020 Jul;26(7):1125-1134. doi: 10.1038/s41591-020-0892-6.