Abstract SY19-01: Identifying and overcoming immune barriers at the level of the tumor microenvironment

Abstract

Abstract Immunotherapeutic approaches for the treatment of melanoma, such as tumor antigen-based vaccines, can frequently boost immune responses as measured in the peripheral blood. However, clinical responses as measured by tumor shrinkage have been observed in only a minority of patients. This observation has prompted careful analysis of the tumor microenvironment to probe for biologic correlates to clinical response and also to identify mechanisms of tumor resistance. Patients with advanced melanoma treated on two different vaccine platforms had pretreatment tumor biopsies analyzed by Affymetrix gene expression profiling. Supervised hierarchical clustering was performed based on favorable or unfavorable clinical outcome. An expanded bank of tumors was also analyzed to increase the sample size and better understand gene patterns that segregate into subtypes. Two major categories of melanoma metastases have been observed. One subgroup of patients has an inflamed phenotype that includes expression of chemokines, T cell markers, and other immunoregulatory factors. Clinical responders to melanoma vaccines appear to fall within this subset. This group also contains the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3, suggesting that these immune suppressive mechanisms may dominantly inhibit antitumor T cell function in those patients. In addition, absence of B7 expression suggests that classical T cell anergy also may be operational. Preclinical experiments have confirmed a critical role for all 4 of these mechanisms in limiting antitumor T cell efficacy in vivo, giving candidate treatment strategies for translation back into the clinic. These include IDO inhibitors, anti-PD-1 mAbs, and approaches to deplete CD25+ Tregs. A second subset of patients is represented by tumors which are noninflamed and lack chemokines for T cell recruitment. Therefore, a major barrier in these cases appears to be failed T cell migration into tumor sites. Experimental strategies to augment T cell migration can have important antitumor effects in preclinical models. Finally, the presence of inflammatory factors was associated with a type I IFN transcriptional signature, and murine experimental models have confirmed a critical role for type I IFN signaling in mediating innate immune “sensing” of a growing tumor in vivo. Our results confirm that molecular profiling of melanoma metastases may be useful as a predictive biomarker for response to melanoma vaccines. In addition, specific features identified in defined subsets of patients offer new therapeutic strategies based on overcoming resistance to immune destruction at the level of the tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY19-01. doi:10.1158/1538-7445.AM2011-SY19-01