Combined adjuvants of poly(I:C) plus LAG‐3‐Ig improve antitumor effects of tumor‐specific T cells, preventing their exhaustion

Abstract

Therapeutic cancer vaccines are designed to treat cancer by boosting the endogenous immune system to fight against the cancer. In the development of clinically effective cancer vaccines, one of the most practical objectives is to identify adjuvants that are capable of optimizing the vaccine effects. In this study, we explored the potential of polyinosinic–polycytidylic acid (poly(I:C)) and LAG‐3‐Ig (soluble recombinant protein of lymphocyte activation gene‐3 [LAG‐3] extracellular domain fused with human IgG Fc region) as adjuvants for P1A tumor antigen peptide vaccine in a pre‐established P815 mouse tumor model with a transfer of tumor‐specific T cells. Whereas the use of poly(I:C) or LAG‐3‐Ig as a signal adjuvant induced a slight enhancement of P1A vaccine effects compared to incomplete Freund's adjuvant, combined treatment with poly(I:C) plus LAG‐3‐Ig remarkably potentiated antitumor effects, leading to complete rejection of pre‐established tumor and long‐term survival of mice. The potent adjuvant effects of poly(I:C) plus LAG‐3‐Ig were associated with an enhanced infiltration of T cells in the tumor tissues, and an increased proliferation and Th1‐type cytokine production of tumor‐reactive T cells. Importantly, the combined adjuvant of poly(I:C) plus LAG‐3‐Ig downregulated expressions of PD‐1, LAG‐3, and TIGIT on P1A‐specific T cells, indicating prevention of T cell exhaustion. Taken together, the results of the current study show that the combined adjuvants of poly(I:C) plus LAG‐3‐Ig with tumor peptide vaccine induce profound antitumor effects by activating tumor‐specific T cells.

Reinforce the antitumor activity of CD8+ T cells via glutamine restriction

“…Tumor-infiltrating lymphocytes were histologically analyzed using sections of frozen tumor tissues as described previously. 29 In brief, tumors were excised from the mice and embedded in O.C.T. compound (cat.# 4583; Sakura Finetek, Tokyo, Japan) to generate frozen sections of tumor tissues.…”

Mini-intronic plasmid vaccination elicits tolerant LAG3+CD8+T cells and inferior antitumor responses

“…37,50 While our findings are consistent with the well documented role of LAG3 as a negative regulator of CD8 C T cell function as described above, it could be viewed to be in contrast to reports describing the strong adjuvant activity of soluble LAG3 fused to the Fc portion of IgG molecules (LAG3-Ig). 51,52 In combination with LAG3-Ig, a DNA vaccine encoding Her-2/neu was able to better protect against an autochthonous breast tumor. 51 Similarly, Kano et al demonstrated the utility of LAG3-Ig as an adjuvant in enhancing antitumor responses upon peptide vaccination in the presence of Poly I:C. 52 Mechanistic studies have found that LAG3-Ig is able to mediate DC activation and maturation through its binding to MHC-II, and it is currently assumed that this is the primary mechanism of immune stimulation.…”

“…51,52 In combination with LAG3-Ig, a DNA vaccine encoding Her-2/neu was able to better protect against an autochthonous breast tumor. 51 Similarly, Kano et al demonstrated the utility of LAG3-Ig as an adjuvant in enhancing antitumor responses upon peptide vaccination in the presence of Poly I:C. 52 Mechanistic studies have found that LAG3-Ig is able to mediate DC activation and maturation through its binding to MHC-II, and it is currently assumed that this is the primary mechanism of immune stimulation. 53 Our studies suggest that an alternative mechanism may be that LAG3 signaling on antigen primed CD8 C T cells is inhibited by saturation of LAG3 binding partners following LAG3-Ig administration, similar to the use of a LAG3-specific blocking antibody.…”

Development of Drugs Based on High-Polymeric Double-Stranded RNA for Antiviral and Antitumor Therapy

“…Kano et al [120] investigated PolyI:PolyC and the recombinant protein encoded by the lymphocyte 3 activation gene (LAG-3) fused to human IgG Fc (LAG-3-Ig) as adjuvants to a peptide vaccine against the tumor antigen P1A. LAG-3 (CD223) is a protein expressed on the membrane of activated T-, B-cells, NK-сells, plasmacytoid DC and plays an important role in their functioning.…”

“…The antitumor effect was due to increased proliferation and infiltration of tumor tissues by T-cells and their production of Th1type cytokines. The combination of PolyI:PolyC with LAG-3-Ig suppressed expression of a number of proteins and receptors on T-cells, preventing their "depletion"; this is important for realization of a deep and long-lasting antitumor immune response [120].…”