Confronting the Challenges of Solid Tumors with Antigen Spreading

Summary

New immunotherapy strategies are needed to counter the challenges imposed by the solid tumor microenvironment. Çuburu et al. have developed a new approach that is independent of tumor antigens and effective in mobilizing and activating various immune cells to target the tumor and promote antigen spreading. Leveraging a mouse model of murine CMV infection (MCMV), the authors demonstrate how pre-existent immunity against a latent virus can be recalled, driving cytotoxicity and antigen spreading to reduce tumor growth (Çuburu et al. 2022).

Background

Cancer immunotherapies, such as autologous or allogeneic cell therapies and cancer vaccines, work by targeting specific tumor antigens. However, in solid tumors, immunotherapies face different challenges limiting their effectiveness. First, the limited availability of genuinely tumor-specific antigens affects immunotherapy efficacy and safety. Second, the solid tumor immunosuppressive microenvironment, mediated by metabolites (e.g., ROS and NO), secreted proteins (e.g., IL-10 and TGF-β), and inhibitory cells (e.g., MDSCs, and Tregs), prevents efficient infiltration and function of adoptively transferred or endogenously activated immune cells (Labani-Motlagh et al. 2020). Lastly, downregulation of targeted antigens or antigen escape is a mechanism driving tumor resistance and is known to limit the long-term efficacy of cell immunotherapies, such as CAR T cells (Hupperetz et al. 2022).

Meanwhile, antigen or epitope spreading helps improve the efficacy of immunotherapies, such as cancer vaccines and adoptively transferred T cells targeting multiple and personalized tumor antigens. Mechanistically, this process is driven by antigens released once activated T cells enact their cytotoxic tumor cell killing. Uptake, processing, and presentation of new tumor-derived epitopes by antigen-presenting cells (APCs) help expand and diversify the T and B lymphocyte anti-tumor response.

Because epitope spreading has been linked to improved clinical outcomes, strategies that exploit this process are of particular interest in the context of solid tumors (Brossart, 2020). Therefore, Çuburu and colleagues have developed and tested a new approach to re-direct pre-existent CMV immunity towards the tumor microenvironment. By introducing CMV antigens directly within tumors, this approach aims to activate pre-existent and non-tumor-specific cytotoxic T cells to promote antigen spread.

To evaluate the potential of this strategy in a human-relevant setting, Çuburu et al. leveraged a mouse model of latent CMV infection. The MCMV model was fitting for these studies because it replicates several features of the CMV infection in humans, including the virus latency, and induced long-lived CD8+ and CD4+ T cell immunity. Additionally, a significant proportion, about 83% of the global population, is estimated to have experienced CMV infection and thus retain immune memory against CMV-derived antigens.

Experiment

To evaluate the effects of epitope spreading on tumor growth, Çuburu et al. induced a latent CMV infection in mice, which were subsequently injected intradermally or subcutaneously with tumor cells. Specifically, model generation involved early infection with murine CMV at 8-10 weeks, with mice receiving tumor cells at a protracted period, after about 4 months, following viral dormancy.

Once tumors reached a predetermined volume, synthetic peptides generated by GenScript with sequences corresponding to CMV-derived peptides, MHC-I or MHC-II restricted, were injected directly into tumors, alone or combined with an adjuvant.  

Result

Çuburu and colleagues leveraged synthetic peptides corresponding to murine CMV epitopes to evaluate anti-CMV T cell responses through in vitro assays. By stimulating peripheral blood mononuclear cells (PBMCs) from CMV-infected mice with a mixture of MHC-I CMV epitopes (i.e.,   IE3, m38, m45, m57, m139, m141, and m164), the authors confirmed the presence of robust CD8+ T cell responses. Weaker CD4+ T cell responses were also stimulated by specific MHC-II restricted CMV derived peptides (i.e., m09 and m139).

Having confirmed the establishment of immunity against murine CMV, a selection of synthetic peptides corresponding to MHC-I or MHC-II restricted CMV sequences were injected directly into tumors. Evaluation of the tumor tissue confirmed the presence of infiltrating CD8+ and CD4+ T cells. In addition, localized cytotoxic activity and tumor cell death occurred following intratumoral administration of MHC-I, but not MHC-II restricted peptides.

Çuburu et al. found that MHC-I and MHC-II/(with adjuvant) CMV-derived peptides promoted tumor infiltration by other immune effector cells, such as macrophages, neutrophils, and NK and B cells. Therefore, CMV-derived peptides effectively drove the tumor microenvironment towards a more active immune state, promoting antigen spreading. Çuburu and colleagues confirmed that the enhanced immune activity associated with intratumoral injection of MHC-I CMV peptides effectively delayed tumor growth and improved survival. Significantly, complete regression could be achieved by combined intratumoral dosing with MHC-I and MHC-II CMV peptides. Lastly, the team provided evidence supporting the occurrence of antigen spreading and its benefits by demonstrating the induction of robust CD8+ T cell responses against tumor-specific antigens and its correlation with long-lasting anti-tumor immunity.

Reference

  • Çuburu N et al. Harnessing anti-cytomegalovirus immunity for local immunotherapy against solid tumors. Proc Natl Acad Sci U S A.(2022) doi: 10.1073/pnas.2116738119.
  • Hupperetz, C., Lah, S., Kim, H. & Kim, C. H. CAR T Cell Immunotherapy Beyond Haematological Malignancy. Immune Network(2022) doi:10.4110/in.2022.22.e6.
  • Labani-Motlagh, A., Ashja-Mahdavi, M. & Loskog, A. The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses. Frontiers in Immunology (2020) doi:10.3389/fimmu.2020.00940.

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