Antigenic targets in clear cell renal cell carcinoma

Abstract

Immune checkpoint inhibitors (ICIs) have transformed the management of advanced renal cell carcinoma (RCC), but most patients still do not receive a long-term benefit from these therapies, and many experience off-target, immune-related adverse effects. RCC is also different from many other ICI-responsive tumors, as it has only a modest mutation burden, and total neoantigen load does not correlate with ICI response. In order to improve the efficacy and safety of immunotherapies for RCC, it is therefore critical to identify the antigens that are targeted in effective anti-tumor immunity. In this review, we describe the potential classes of target antigens, and provide examples of previous and ongoing efforts to investigate and target antigens in RCC, with a focus on clear cell histology. Ultimately, we believe that a concerted antigen discovery effort in RCC will enable an improved understanding of response and resistance to current therapies, and lay a foundation for the future development of "precision" antigen-directed immunotherapies.

Keywords: Renal cell carcinoma; T cell receptor; cancer vaccine; chimeric antigen receptor T cell; neoantigen; tumor antigen.

Fig. 1

Overview of the cancer immunity cycle (as described by Chen and Mellman). The seven steps of the cancer immunity cycle are displayed in a cyclic format. In the first step, tumor cells undergo immunogenic cell death. Death of the malignant cells allows antigens to be released into the microenvironment. These antigens are taken up by antigen presenting cells, such as naïve dendritic cells; trafficked to lymph tissue; and processed with the internal antigen processing machinery. This involves proteosomes cleaving antigens into smaller peptides and presenting them on HLA complexes. Activated antigen presenting cells display antigens to prime and activate naïve T cells. The activated T cells differentiate into specific classes depending on factors such as co-stimulatory signals. Activated T cells migrate back to the site of the tumor via trafficking signals and infiltrate the tumor microenvironment. Once inside the tumor, T cells may recognize and kill malignant cells, thereby restarting the cycle.

Fig. 2

Antigen Classes. Antigens may be categorized as HLA-restricted or surface antigens. HLA-restricted antigens include all proteins generated within the cell that are processed by antigen presenting machinery. Surface antigens are a subset of proteins that are presented on the surface of the cell. Each class of antigen has been targeted by antigen-directed therapies in a personalized or universal basis. Personalized therapies are unique to each patient and have the opportunity to create a deeper immune response to malignancy. Universal therapies are not unique to an individual patient, but are cost effective and available immediately as an “off-the-shelf” therapy.