The Weichselbaum lab seeks to improve cancer treatment through elucidating the mechanisms of cancer proliferation, metastasis, and therapeutic resistance. Our multi-front approach reflects the complex interplay of factors and their pathologic and immunologic consequences.
The Weichselbaum Lab is renowned for landmark translational and clinical investigations involving the potentially curative treatment of a limited number of metastasis (termed “oligometastasis”) with radiotherapy and defining the biological basis of these limited metastases. Investigators from the Weichselbaum Lab have also led the field in the integration of immune modifiers with radiotherapy and other cytotoxic therapies. Related basic and translational research areas include examination of the tumor microenvironment, as well as host factors to investigate how radiation alleviates tumor immunosuppression and how radiotherapy can best be integrated with immune checkpoint therapies and therapeutic vaccines.
In recent years the Weichselbaum lab has contributed significantly to understanding the effect of ionizing radiation (IR) on the tumor microenvironment.
High-dose ionizing irradiation (IR) results in direct tumor cell death and augments tumor-specific immunity, which enhances both local and distant tumor control. IR-mediated tumor regression depends on type I interferon (IFN) and the adaptive immune response. We have demonstrated that STING signaling in dendritic cells (DCs) is required for IFN induction and the antitumor immune response following radiotherapy. We have further identified the biological basis and role of non-canonical NF-kB signaling, host microbiota-derived metabolites, and the RNA sensing RIG-I-like receptor LGP2 in the priming capacity of DCs and radiation-mediated antitumor immunity. These findings provide new therapeutic strategies to enhance the response to radiotherapy.
Radioresistance and local relapses often occur following radiotherapy. We have demonstrated that radiation can induce PD-L1 in the tumor microenvironment and impair antitumor immunity. The combination of radiotherapy and anti-PD-L1 synergistically reduced tumor-infiltrating myeloid-derived suppressor cells (MDSC). We also identified that STING/IFN activation after radiation can suppress inflammation through recruiting myeloid cells via CCR2. In order to overcome barriers to successful treatment, we investigated the potential for oral all-trans retinoic acid (ATRA) as a means of reprogramming intratumoral myeloid cells and enhancing systemic antitumor immunity. The combination of ATRA and radiotherapy induced inflammatory macrophages and enhanced the antitumor T-cell response. These findings highlight the intricate balance between radiation, T cells, MDSCs, and the PD-L1/PD-1 axis, and establish a basis for the rational design of combination treatment with immune modulators and radiotherapy.
Successful combinations of radiotherapy and immunotherapy depend on the presence of live T cells within the tumor; however, radiotherapy is believed to damage T cells. Using longitudinal in vivo imaging and functional analysis, we reported that a large proportion of T cells survive clinically-relevant doses of radiation and show increased motility, and higher production of interferon gamma, compared with T cells from unirradiated tumors. These irradiated intratumoral T cells can mediate tumor control without newly-infiltrating T cells. These findings have implications for the design of radio-immunotherapy trials in that local irradiation is not inherently immunosuppressive, and irradiation of multiple tumors might optimize the systemic effects of radiotherapy.
Tumor-induced CD45–Ter119+CD71+ erythroid progenitor cells, termed “Ter cells,” promote tumor progression by secreting artemin (ARTN), a neurotrophic peptide that activates REarranged during Transfection (RET) signaling. We demonstrated that both local tumor ionizing radiation (IR) and anti-programmed death ligand 1 (PD-L1) treatment decreased tumor-induced Ter cell abundance in mice and demonstrate an out-of-field, or ‘abscopal’ effect mediated by adaptive antitumor immunity. Our results identify multiple targets to potentially improve outcomes after radiotherapy and immunotherapy.