Therapeutic immunization and local low‐dose tumor irradiation, a reinforcing combination

Abstract

Therapeutic cancer vaccines show promise in preclinical studies, yet their clinical efficacy is limited. Increased recruitment of immune cells into tumors and suppression of the immune suppressive tumor environment are critical components toward effective cancer immunotherapies. Here, we report how local low-dose irradiation, alone or with a therapeutic immunization based on Semliki Forest virus (SFV) against human papillomavirus (HPV)-related cancer, influences these immune mechanisms. We first demonstrated that immunization with SFVeE6,7 or SFVeOVA, replicon particles expressing either HPV16 E6/E7 or ovalbumin, resulted in an antigen-specific migration of CD81 T cells into HPV-and OVA-specific tumors. Local low-dose tumor irradiation alone resulted in a 2-fold increase of intratumoral CD81 T cells. When 14 Gy irradiation was combined with immunization, intratumoral numbers of CD81 T cells increased 10-fold and the number of CD81 T cells specific for the E7-epitope increased more than 20-fold. Irradiation alone however also increased the number of intratumoral myeloid-derived suppressor cells (MDSCs) 3.5-fold. Importantly, this number did not further increase when combined with immunization. As a result, the ratio of antigen-specific CD81 T cells and MDSCs in tumors increased up to 85-fold compared to the control. We furthermore demonstrated that following irradiation CCR2 and CCL2, CXCR6 and CCL16, chemokines and ligands involved in tumor homing of immune cells, were significantly up regulated. This study demonstrates that local low-dose tumor irradiation influences the intratumoral immune population induced by SFVeE6,7 immunization by a strong increase in the ratio of antitumoral to immune suppressive cells, thus changing the intratumoral immune balance in favor of antitumor activity.An essential requirement for cancer immunotherapy is activation of antigen-specific T cells and their homing into tumors. Although antitumoral immunization studies in the clinic report the presence of vaccine-induced antigen-specific T cells in periphery or at the injection site, so far the therapeutic antitumor responses are limited. [1][2][3][4] The most obvious reasons for the lack of clinical responses can be insufficient tumor infiltration of antigen-specific immune effector cells and the immunosuppressive environment of the tumor. [5][6][7][8][9] Strategies aiming at promoting T-cell influx into the tumor or at reverting the immune suppression within the tumor microenvironment are currently the focus of numerous preclinical studies. In a recent review, we addressed various antitumoral therapeutic strategies currently under investigation.

Human cytotoxic T-lymphocyte membrane-camouflaged nanoparticles combined with low-dose irradiation: a new approach to enhance drug targeting in gastric cancer

“…30,31 Recently, low-dose radiotherapy has been reported to safely control gastric cancer-related symptoms, demonstrating significant clinical utility. 29 Previous studies have demonstrated that local low-dose irradiation (LDI) alone resulted in an increase in intratumoral CD8+ T cells, 32 which was shown to be correlated with the upregulated expression of adhesion molecules on tumor vasculature and the increased expression of chemoattractants. 33 Furthermore, local LDI could promote the normalization of aberrant vasculature, which facilitated the entry of T lymphocytes into tumors.…”

“…Numerous studies have also identified that local LDI induces recruitment of tumor-specific T lymphocytes to the tumor site, but focused only on the cell behavior. 32,34,46 Therefore, this is the first study to use local irradiation, which is one of the most commonly used treatment modalities for gastric cancer, as a chemoattractant for a hCTL membrane-based drug delivery system.…”

Noninvasive monitoring of cancer therapy induced activated T cells using [18F]FB-IL-2 PET imaging

“…7 This difference may be accounted for by differences IL-2 receptor levels expressed on activated T cells and by IL-2 receptor expression on other infiltrating lymphocytes, such as natural killer cells. The synergistic increase in tracer accumulation was also observed in immunerelated organs.…”

“…Our viral vector is based on recombinant Semliki Forest virus (rSFV) encoding a fusion protein of E6 and E7 derived from human papilloma virus (HPV) type 16 (rSFVeE6,7). 6 In combination with local irradiation, immunization with rSFVeE6,7 in tumor-bearing mice demonstrated a synergistic antitumor effect.…”

“…6 In combination with local irradiation, immunization with rSFVeE6,7 in tumor-bearing mice demonstrated a synergistic antitumor effect. 7 These synergistic effects culminates from mechanisms such as trafficking of activated tumor-infiltrating lymphocytes (TILs) to the tumor site, upregulation of tumor antigens for TIL recognition and induction of positive immune modulatory pathways.…”