Low doses of gamma irradiation potentially modifies immunosuppressive tumor microenvironment by retuning tumor-associated macrophages: lesson from insulinoma

Abstract

Tumor infiltrating iNOS+ macrophages under the influence of immunosuppressive tumor microenvironment gets polarized to tumor-promoting and immunosuppressive macrophages, known as tumor-associated macrophages (TAM). Their recruitment and increased density in the plethora of tumors has been associated with poor prognosis in cancer patients. Therefore, retuning of TAM to M1 phenotype would be a key for effective immunotherapy. Radiotherapy has been a potential non-invasive strategy to improve cancer immunotherapy and tumor immune rejection. Irradiation of late-stage tumor-bearing Rip1-Tag5 mice twice with 2 Gy dose resulted in profound changes in the inflammatory tumor micromilieu, characterized by induction of M1-associated effecter cytokines as well as reduction in protumorigenic and M2-associated effecter cytokines. Similarly, in vitro irradiation of macrophages with 2 Gy dose-induced expression of iNOS, NO, NFκBpp65, pSTAT3 and proinflammatory cytokines secretion while downregulating p38MAPK which are involved in iNOS translation and acquisition of an M1-like phenotype. Enhancement of various M2 effecter cytokines and angiogenic reprogramming in iNOs+ macrophage depleted tumors and their subsequent reduction by 2 Gy dose in Rip1-Tag5 transgenic mice furthermore demonstrated a critical role of peritumoral macrophages in the course of gamma irradiation mediated M1 retuning of insulinoma.

Modulating Both Tumor Cell Death and Innate Immunity Is Essential for Improving Radiation Therapy Effectiveness

“…However, there were also studies showing that radiation therapy could redirect TAMs from protumorigenic to antitumoral cells. For example, low-dose (2 Gy) whole-body irradiation induced iNOS expression and the production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IL-12 (p70), and IFN-γ in peritoneal macrophages and TAMs (120). A recent study on murine insulinoma demonstrated that low-dose (2 Gy) irradiation induced iNOS expression in macrophages both in vitro and in vivo .…”

Macrophages directed approaches are paramount for effective cancer immunotherapies

“…For this point of view, M1 effector phenotype of macrophage thus represent the most suitable target cell populations for rendering tumor directed therapeutic interventions more effective. Histo-pathological analysis of several tumors revealed that around 50% of the tumor mass is composed of leukocyte among which T-lymphocytes and macrophages represent the major proportion Figure 1, thus reflecting the signals from the microenvironment they dwell in [90,91]. Classically activated macrophages are immunostimulatory with Th1-orienting properties while M2 are immunoregulatory with Th2 immune response [92].…”

“…Classically activated macrophages are immunostimulatory with Th1-orienting properties while M2 are immunoregulatory with Th2 immune response [92]. Tumor polarized macrophages are referred as tumor-associated macrophage (TAM) [93,94], which exhibits several pro-tumoral functions, mentioned above [90,95]. TAM accumulation in majority of tumours and subsequent phenomenal changes being a major hurdle resulting in poor cancer prognosis, macrophage depletion, e.g.…”

“…In similar lines, targeting TAM by acting on molecular pathways for TAM polarization such as NF-κB, STAT3 and HIF-1 which are considered to be the master regulators of TAM transcriptional programmes represent another potential therapeutic option. We have recently shown the therapeutic [90,91] and demonstrated that LDI had an impact on tuning TAM M2 to M1 phenotype thus aiding in tumor directed T cell infiltration and subsequent tumour rejection in neuro-endocrine pancreatic tumour mice model (Figure 2). In similar lines, systemic irradiation also contributed for normalising tumor vasculature in a macrophage dependent manner [90].…”

“…We have recently shown the therapeutic [90,91] and demonstrated that LDI had an impact on tuning TAM M2 to M1 phenotype thus aiding in tumor directed T cell infiltration and subsequent tumour rejection in neuro-endocrine pancreatic tumour mice model (Figure 2). In similar lines, systemic irradiation also contributed for normalising tumor vasculature in a macrophage dependent manner [90]. Interestingly, single adoptive transfer of macrophages from systemically irradiated mice with LDI also resulted in enhanced cellular immunity in tumor bearing recipient mice in the absence of external radiation suggesting that systemic radiation with LDI is vital for macrophage retuning from M2 to M1 which is the current need of tumor directed therapies.…”