A heat shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth

Gleisner, María Alejandra; Pereda, Cristián; Tittarelli, Andrés; Navarrete, Mariela; Fuentes, Camila; Avalos, Ignacio; Tempio, Fabián; Araya, Juan Pablo; Becker, María Inés; González, Fermín E.; Lopez, Mercedes N.; Salazar-Onfray, Flavio

Keywords: melanoma, immunotherapy, cancer vaccines, Tumor Lysates, Danger associated molecular patterns (DAMPs)


Background: Immune checkpoint blocker (ICB)-therapy has shown survival benefits for some cancer patients. Nevertheless, many individuals remain refractory or acquire resistance to treatment, motivating the exploration of complementary immunotherapies. Accordingly, cancer vaccines become an attractive alternative since are well tolerated and have moderated, if any, side effects. Optimal delivery of multiple tumor-associated antigens combined with potent adjuvants seems to be crucial for vaccine effectiveness. Methods: Here, a prototype for a generic melanoma vaccine, named TRIMELVax, was tested using B16F10 mouse melanoma model. This vaccine is made of heat shock-treated tumor cell lysates combined with the Concholepas concholepas hemocyanin as adjuvant. Results: While B16F10 lysate provides appropriate melanoma-associated antigens, both a generic human melanoma cell lysate and hemocyanin adjuvant contributes with danger signals promoting conventional dendritic cells type 1 (cDC1), activation, phagocytosis and effective antigen cross-presentation. TRIMELVax inhibited tumor growth and increased mice survival, inducing cellular and humoral immune responses. Furthermore, this vaccine generated an increased frequency of intratumor cDC1s but not cDC2s. Augmented infiltration of CD3+, CD4+ and CD8+ T cells was also observed, compared with anti-PD-1 monotherapy, while TRIMELVax/anti-PD-1 combination generated higher tumor infiltration of CD4+ T cells. Moreover, TRIMELVax promoted an augmented proportion of PD-1lo CD8+ T cells in tumors, a phenotype associated to prototypic effector cells required for tumor growth control, preventing dysfunctional T cell accumulation. Conclusions: The therapeutic vaccine TRIMELVax efficiently controls the weakly immunogenic and aggressive B16F10 melanoma tumor growth, prolonging tumor-bearing mice survival even in the absence of ICB. The strong immunogenicity shown by TRIMELVax encourages clinical studies in melanoma patients.

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Título de la Revista: Journal for ImmunoTherapy of Cancer
Editorial: BMJ Publishing Group
Fecha de publicación: 2020
Idioma: Inglés