A Process Underlying Acquired Resistance to Immunotherapy
Cancer immunoediting, a process unifying the host-protecting and tumour-promoting functions, has emerged as a means through which tumour heterogeneity can be shaped and evolved 1. A T cell-dependent selection process came to light as a mechanism of cancer immunoediting, where the heterogeneity of tumour is moulded by the recognition of tumour-specific antigens and elimination of specific immunogenic tumour clones, thus rendering tumours more homogeneous1.
Numerous animal models and some human studies provided insights into the basis of cancer immunoediting, which entails three distinct dynamic stages, such as detection and elimination of antigenic cancer clones by innate and adaptive immunity; equilibrium of tumour clone outgrowth; and an escape phase when tumours with reduced immunogenicity are primed to expansion and growth in an immunosuppressive tumour microenvironment1.
Efficacy of cancer immunotherapies, such as T cell checkpoint blockade and adoptive T cell therapy, most likely rely on neoantigens that are generated as a consequence of genetic mutations and large genomic alterations, both at the core of plasticity of tumour molecular phenotypes. Strategies to selectively enhance T cell reactivity against defined neoantigens are becoming ever more important.
Recent human studies provided important insights into the longitudinal progression of the neoantigen landscape in response to immunotherapies. In one of the studies, the stability of neoantigen-specific T cell responses and the antigen repertoire was analysed in two patients with stage IV melanoma treated by adoptive T cell transfer2. The total reduced expression of genes in one case or a loss of the mutant alleles in two cases led to elimination of T cell-recognised neoantigens from tumour cell populations2. This study has provided evidence that T cells are involved in cancer neoantigen immunoediting.
The immune checkpoint inhibitors show significant efficacy in patients with tumours that contain increased mutation-associated neoantigen load. Another study examined the evolution of tumour neoantigens prior to and during the treatment of four patients from a cohort of 42 patients with non-small cell lung cancer receiving anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies, who initially responded to treatment, but later therapy-resistant tumour outgrowth has emerged3. Matched pre-treatment and resistant tumours showed genomic changes that led to elimination of 7–18 putative neoantigens, as shown by their immunogenicity in autologous T cell cultures, suggesting that these subclones were eliminated from the tumour during treatment with the immune checkpoint blockers. Tumour neoantigen elimination has occurred through two distinct mechanisms3. The first required immune elimination of neoantigen-containing tumour cells representing a subpopulation within the tumour and the outgrowth of remaining cells3. The second mechanism implicated deletions of chromosomal regions with truncal alterations3. In addition, loss of neoantigens led to a decrease in clonality of cytotoxic T cell receptor clonotypes, thus demonstrating that tumour immune evasion clearly contributes to a resistant phenotype3. This study proved that ever-changing mutational topography during the immune checkpoint blockade is at the core of a switch to acquired resistance to treatment. Therefore, expanding the extent of neoantigen reactivity may help to lessen the degree of escape from effective treatment.
Development of efficacious patient-tailored cancer immunotherapies will rely on untangling the genomic mechanisms through which cancer evades anti-tumour immune responses. Identification of neoantigens before and at the point of emergence of resistance will be of critical importance in developing patient-specific immunotherapeutic strategies.
1Vesely MD and Schreiber RD. Cancer immunoediting: antigens, mechanisms and implications to cancer immunotherapy. Ann N Y Acad Sci. 2013;1284(1):1–5
2Verdegaal EM, et al. Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature. 2017; 536(7614):91–5
3Anagnostou V, et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 2017;7(3):264–76