Tumor Microenvironment Remodeling by Intratumoral Oncolytic Vaccinia Virus Enhances the Efficacy of Immune-Checkpoint Blockade

Abstract

Purpose: Cancer immunotherapy is a potent treatment modality, but its clinical benefit depends on the tumor's immune profile. Here, we used mJX-594 (JX), a targeted and GM-CSF-armed oncolytic vaccinia virus, as a strategy to remodel the tumor microenvironment (TME) and subsequently increase sensitivity to aPD-1 and/or aCTLA-4 immunotherapy.Experimental Design: The remodeling of the TME was determined using histologic, flow-cytometric, and NanoString immune profiling analyses. JX was intratumorally injected into implanted Renca kidney tumors or MMTV-PyMT transgenic mouse breast cancers with or without aPD-1 and/or aCTLA-4. Various combination regimens were used to evaluate immunotherapeutic anticancer responses.Results: Intratumoral injection of JX remodeled the TME through dynamic changes in the immune system, as shown by increased tumor-infiltrating T cells and upregulation of immune-related gene signatures. This remodeling induced conversion of a noninflamed tumor into an inflamed tumor. JX virotherapy led to enhanced abscopal effects in distant tumors, with increased intratumoral infiltration of CD8 þ T cells. A depletion study revealed that GM-CSF is an indispensable regulator of anticancer efficacy of JX. Dualcombination therapy with intratumoral JX and systemic aPD-1 or aCTLA-4 further enhanced the anticancer immune response, regardless of various treatment schedules. Of note, triple combination immunotherapy with JX, aPD-1, and aCTLA-4 elicited the most potent anticancer immunity and induced complete tumor regression and long-term overall survival.Conclusions: Our results show that intratumoral JX treatment induces dramatic remodeling of the TME and more potently suppresses cancer progression with immunecheckpoint blockades by overcoming resistance to immunotherapy.

STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade

“…Vascular STING expression in tumor tissue correlated with favorable prognosis in human malignancies, stroma, they may not fully represent the biology of a real tumor immune microenvironment. Therefore, we employed a spontaneous breast cancer model, MMTV-PyMT, which has more mature tumor vasculatures and abundant stromal cells and is therefore a reliable representative of human breast cancer (30,31), to further validate the efficacy of STING activation in combination with VEGFR2 blockade and immune checkpoint inhibition (Figure 10A). After 3 weeks of treatment, RR-CDA alone remarkably delayed tumor growth, not just in the STING-injected tumor, but also in the noninjected tumors, suggesting abscopal antitumor effects upon STING activation; this was further strengthened by adding VEGFR2 blockade (S + V), and the triple combination therapy of RR-CDA, DC101, and anti-PD1 antibody (S + V + P) displayed the most potent tumor growth inhibition effect ( Figure 10, B and C).…”

oHSV2 Can Target Murine Colon Carcinoma by Altering the Immune Status of the Tumor Microenvironment and Inducing Antitumor Immunity

“…5 Increasing evidence has shown that OVs stimulate a series of antitumor immune responses, leading to immunogenicity in the TME and regulation of the immunosuppressive TME. 6 Tumor cell lysis results in the release of tumor-associated antigens (TAAs) and simultaneous expression of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), which stimulate innate immune receptors on professional antigen-presenting cells (APCs). 7,8 OVs can promote the antitumor T cell response through various mechanisms.…”

CENPF driven lung adenocarcinoma and lung squamous cell carcinoma with immune infiltrates

“…Moreover, the correlation between CENPF expression and the marker genes of immune cells implicate the role of CENPF in tumor immunotherapy in LUAD and LUSC. The tumormicroenvironment(TME) plays a key role in the occurrence and development of tumors, and immune infiltration is one of the most important features [17,18]. In addition, the latest research found that tumor immune cell infiltration significantly affects the prognosis and efficacy of immunotherapy, mainly including tumor macrophages and neutrophils infiltrating [19,20].…”