Antigen Spreading Contributes to MAGE Vaccination-Induced Regression of Melanoma Metastases

Abstract

A core challenge in cancer immunotherapy is to understand the basis for efficacious vaccine responses in human patients. In previous work we identified a melanoma patient who displayed a low-level antivaccine cytolytic T-cell (CTL) response in blood with tumor regression after vaccination with melanoma antigens (MAGE). Using a genetic approach including T-cell receptor b (TCRb) cDNA libraries, we found very few antivaccine CTLs in regressing metastases. However, a far greater number of TCRb sequences were found with several of these corresponding to CTL clones specific for nonvaccine tumor antigens, suggesting that antigen spreading was occurring in regressing metastases. In this study, we found another TCR belonging to tumorspecific CTL enriched in regressing metastases and detectable in blood only after vaccination. We used the TCRb sequence to detect and clone the desired T cells from tumor-infiltrating lymphocytes isolated from the patient. This CD8 clone specifically lysed autologous melanoma cells and displayed HLA-A2 restriction. Its target antigen was identified as the mitochondrial enzyme caseinolytic protease. The target antigen gene was mutated in the tumor, resulting in production of a neoantigen. Melanoma cell lysis by the CTL was increased by IFN-g treatment due to preferential processing of the antigenic peptide by the immunoproteasome. These results argue that tumor rejection effectors in the patient were indeed CTL responding to nonvaccine tumor-specific antigens, further supporting our hypothesis. Among such antigens, the mutated antigen we found is the only antigen against which no T cells could be detected before vaccination. We propose that antigen spreading of an antitumor T-cell response to truly tumor-specific antigens contributes decisively to tumor regression. Cancer Res; 71(4); 1253-62. Ó2011 AACR.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…3) shared by normal tissue, which thereby leads to loss of tolerance and autoimmunity. ES has been documented in patients receiving tumor vaccines 41 and in patients who have undergone adoptive transfer (Box 1) of CTLs and CAR T cells 42,43 . Checkpoint therapy with ipilimumab can induce ES 44 , and it is likely that neoantigen-directed immune responses against tumors, when followed by ES, can trigger autoimmunity against nonmalignant tissues in which the neoantigens are absent.…”

Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue

“…The same was true concerning antigen-specific IFN-g production after challenge with Mtb (data not shown), suggesting that detection of antigen-specific immune responses in the peripheral circulation may not reflect the in situ situation, a situation that is appreciated in gauging antitumorspecific cellular immune responses: T-cell specificity mediating tumor regression in situ is very low in PBMCs and is not identical with the immunizing antigen. 29,30 However, we were able to detect stronger induction of proinflammatory cytokines by rBCG vs BCG in PBMCs (Supplementary Table S1). A more proinflammatory milieu at the time of priming may drive quantitatively and qualitative different cellular immune responses with the capacity to home into Mtb-infected tissues.…”

Analysis of the Processing of Seven Human Tumor Antigens by Intermediate Proteasomes

“…This has implication for cancer immunotherapy. For instance, a number of tumor Ags that are relevant for tumor rejection are better-sometimes exclusively-produced by the immunoproteasome, particularly those Ags that are targeted by T lymphocytes elicited by Ag spreading, which relies on presentation of tumor Ags by dendritic cells, which contain mostly immunoproteasomes (13,23). But tumor cells that are not located at inflammatory sites usually do not contain immunoproteasomes, and would therefore not be sensitive to the attack by those T cells.…”