Thymosin α1 reverses oncolytic adenovirus-induced M2 polarization of macrophages to improve antitumor immunity and therapeutic efficacy.

Although oncolytic adenoviruses are widely studied for their direct oncolytic activity and immunomodulatory role in cancer immunotherapy, the immunosuppressive feedback loop induced by oncolytic adenoviruses remains to be studied. Here, we demonstrate that type V adenovirus (ADV) induces the polarization of tumor-associated macrophages (TAMs) to the M2 phenotype and increases the infiltration of regulatory T cells (Tregs) in the tumor microenvironment (TME). By selectively compensating for these deficiencies, thymosin alpha 1 (Tα1) reprograms "M2-like" TAMs toward an antitumoral phenotype, thereby reprogramming the TME into a state more beneficial for antitumor immunity. Moreover, ADVTα1 is constructed by harnessing the merits of all the components for the aforementioned combinatorial therapy. Both exogenously supplied and adenovirus-produced Tα1 orchestrate TAM reprogramming and enhance the antitumor efficacy of ADV via CD8+ T cells, showing promising prospects for clinical translation. Our findings provide inspiration for improving oncolytic adenovirus combination therapy and designing oncolytic engineered adenoviruses.

Liu K ，Kong L ，Cui H ，Zhang L ，Xin Q ，Zhuang Y ，Guo C ，Yao Y ，Tao J ，Gu X ，Jiang C ，Wu J ... -  《-》

Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses.

Watanabe K ，Luo Y ，Da T ，Guedan S ，Ruella M ，Scholler J ，Keith B ，Young RM ，Engels B ，Sorsa S ，Siurala M ，Havunen R ，Tähtinen S ，Hemminki A ，June CH ... -  《JCI Insight》

Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples.

Scott EM ，Jacobus EJ ，Lyons B ，Frost S ，Freedman JD ，Dyer A ，Khalique H ，Taverner WK ，Carr A ，Champion BR ，Fisher KD ，Seymour LW ，Duffy MR ... -  《Journal for ImmunoTherapy of Cancer》

Combining IL-10 and Oncolytic Adenovirus Demonstrates Enhanced Antitumor Efficacy Through CD8(+) T Cells.

Oncolytic viruses are of growing importance in cancer therapeutics since they combine direct oncolytic effect and the stimulation of antitumor immunity. Emerging evidences showed that the function of oncolytic viruses is dependent on immune response in tumor microenvironment, and the modulation of immunity could influence their efficacy. Here we combined the interleukin 10 (IL-10) and oncolytic adenovirus Ad-hTERT to treat lung cancer and explored the underlying mechanism under combination therapy. Lewis lung carcinoma (LLC) and B16F10 tumor-bearing immunocompetent C57BL/6 mice that received Ad-hTERT or IL-10 alone showed mild antitumor effect, while the combination therapy shrink tumor bulks and prolonged survival remarkably. In addition, IL-10 didn't show direct influence on tumor cell viability or Ad-hTERT mediated tumor cell lysis in vitro. To further explore the influence of combination therapy mediated antitumor capacity, we eliminated CD8+ T, CD4+ T or natural killer (NK) cells in LLC and B16F10-bearing C57BL/6 mice, and found that CD8+ T cells were critical mediator in the combination therapy. The combination therapy induced intensive infiltration of CD8+ T cells in tumors, increased tumor-specific IFN-γ secretion by CD8+ T cells. The long-term tumor-specific immune memory induced by the combination therapy rejected rechallenge by respective tumor cell lines. This study demonstrated that the therapy combining IL-10 and Ad-hTERT augmented antitumor efficacy which was CD8+ T cells dependent. Our findings paved the way to combine cytokines and oncolytic viruses to enhance antitumor immunotherapy in treating cancer.

Chen D ，Huang L ，Zhou H ，Zhang Y ... -  《-》

SHISA3 Reprograms Tumor-Associated Macrophages Toward an Antitumoral Phenotype and Enhances Cancer Immunotherapy.

The main challenge for immune checkpoint blockade (ICB) therapy lies in immunosuppressive tumor microenvironment (TME). Repolarizing M2-like tumor-associated macrophages (TAMs) into inflammatory M1 phenotype is a promising strategy for cancer immunotherapy. Here, this study shows that the tumor suppressive protein SHISA3 regulates the antitumor functions of TAMs. Local delivery of mRNA encoding Shisa3 enables cancer immunotherapy by reprogramming TAMs toward an antitumoral phenotype, thus enhancing the efficacy of programmed cell death 1 (PD-1) antibody. Enforced expression of Shisa3 in TAMs increases their phagocytosis and antigen presentation abilities and promotes CD8+ T cell-mediated antitumor immunity. The expression of SHISA3 is induced by damage/pathogen-associated molecular patterns (DAMPs/PAMPs) in macrophages via nuclear factor-κB (NF-κB) transcription factors. Reciprocally, SHISA3 forms a complex with heat shock protein family A member 8 (HSPA8) to activate NF-κB signaling thus maintaining M1 polarization of macrophages. Knockout Shisa3 largely abolishes the antitumor efficacy of combination immunotherapy with Toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) and PD-1 antibody. It further found that higher expression of SHISA3 in antitumoral TAMs is associated with better overall survival in lung cancer patients. Taken together, the findings describe the role of SHISA3 in reprogramming TAMs that ameliorate cancer immunotherapy.

Zhang S ，Yu B ，Sheng C ，Yao C ，Liu Y ，Wang J ，Zeng Q ，Mao Y ，Bei J ，Zhu B ，Chen S ... -  《Advanced Science》