Abstract
Mycobacterium bovis bacille Calmette–Guérin (BCG) is listed as an intralesional (IL) therapeutic option for inoperable stage III in-transit melanoma in the National Comprehensive Cancer Network Guidelines. Although the mechanism is unknown, others have reported up to 50% regression of injected lesions, and 17% regression of uninjected lesions in immunocompetent patients after direct injection of BCG into metastatic melanoma lesions in the skin. BCG and other mycobacteria express ligands capable of stimulating the γ9δ2 T cells. Therefore, we hypothesized that γ9δ2 T cells play a role in promoting BCG-mediated antitumor immunity in patients treated with IL-BCG for in-transit cutaneous melanoma metastases. Indeed, we found γ9δ2 T cell infiltration in melanoma skin lesions during the course of IL-BCG treatment. Gene expression analysis revealed that BCG injection elicits the expression of a vast array of chemokines in tumor lesions, including strong expression of CXCL9, 10, and 11, a set of chemokines that attract T cells expressing the CXCR3 chemokine receptor. In corroboration with our hypothesis, approximately 85% of γδ T cells express high levels of CXCR3 on their surface. Importantly, the injected tumor lesions also express genes whose protein products are the antigenic ligands for γδ T cells (BTN3A1 and MICB), and the cytokines that are the typical products of activated γδ T cells. Interestingly, we also found that γδ T cells infiltrate the regressed lesions that did not receive BCG injections. Our study suggests that γ9δ2 T cells may contribute to melanoma regression induced by IL-BCG treatment.
Highlights
IntroductionIn contrast to most other types of cancer in which incidences are steadily declining, the incidence of melanoma continues to climb, especially in young patients [1]
Melanoma is a cutaneous malignancy that kills ~10,000 people annually in the US [1]
IL-bacille Calmette–Guérin (BCG) Induces Melanoma Regression Accompanied by γδ T Cell Infiltration
Summary
In contrast to most other types of cancer in which incidences are steadily declining, the incidence of melanoma continues to climb, especially in young patients [1]. BCG and Cutaneous Melanoma Metastases protective role of immune cells against melanoma. Intralesional (IL) Mycobacterium bovis bacille Calmette–Guérin (BCG), or IL-BCG, is currently a recommended therapy in the National Comprehensive Cancer Network (NCCN) Guidelines (version 1.2017) for inoperable stage III in-transit metastatic melanoma. Direct injection of BCG into metastatic melanoma lesions in the skin has resulted in up to 90% regression of injected lesions and 17% regression of uninjected lesions in immunocompetent patients [5, 6]. Epidermal injection of BCG induces a typical delayed hypersensitivity response, characterized by numerous chemokines and cytokines and recruitment of a vast array of immune cells into the BCG injected sites [7]. It is well accepted that the immune response plays an important role in IL-BCGinduced tumor regression
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