Improvement of Antitumor Therapies Based on Vaccines and Immune-Checkpoint Inhibitors by Counteracting Tumor-Immunostimulation

Abstract

Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors), counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth.

Inhibition of hyperprogressive cancer disease induced by immune-checkpoint blockade upon co-treatment with meta-tyrosine and p38 pathway inhibitor

“…In consequence, it might exert a boosting and adjuvant like-effect on the antitumor immune response. On the other hand, a specific inhibitor of p38 pathway might counteract the tumor-accelerating effect induced by ICI on the basis that, in a former paper [16], we have suggested that the enhancing effect induced by a weak antitumor immune response was associated with the activation of TLR4 and p38 signaling pathways in macrophages recruited at the tumor place.…”

“…The following antibodies were used: anti-p-STAT3, anti-STAT3 (Santa Cruz Biotechnology, Paso Robles, CA), anti-p38 (Santa Cruz Biotechnology) and anti-βactin (Cell Signaling Technology, Danvers, MA). Levels of each band were normalized with β actin densitometry units as reported [16].…”

“…1E and F). In turn, MC-C tumor exhibited low constitutive expression of phosphorylated STAT3 (pSTAT3) -an activated molecule that is involved in the transcription of genes that induce tolerogenic and immunosuppressive signals [16]; (Fig. 2A and B ) -and low expression of surface PD-L1 in tumor cells and tumor infiltrating cells (Fig.…”

“…The second argument is related to the fact that immune-checkpoint inhibitors (ICI) were truly effective in restraining experimental murine tumors, although only when they faced incipient tumors. Afterwards, as the tumor becomes larger, and resembles the size that could usually be detectable at first clinical inspection, null, or even stimulatory effects on tumor growth have been observed [16].…”

“…To account for this aim, we have considered the possibility that the antitumor immune response may be not linear -as orthodoxy predicts-but biphasic -as the immunostimulatory theory of cancer states-with strong immune responses producing inhibition while weak ones inducing stimulating effects on tumor growth (Suppl. Figure 1) [16,18,19,20]. We suggest that ICI treatment on large tumors produces a weak tumor-stimulating antitumor immune response.…”