JITC Editor Picks
Xia Liu, Fusheng Si, David Bagley, Feiya Ma, Yuanqin Zhang, Yan Tao, Emily Shaw, Guangyong Peng
Journal for ImmunoTherapy of Cancer 2022;10:e005020 (3 October 2022)
RESEARCH
Summary:
Multiple mechanisms beyond exhaustion alone contribute to T cell dysfunction in the tumor microenvironment. Xia Liu and colleagues provide preclinical evidence that alleviation of T cell senescence via inhibition of AMK or MAPK signaling leads to enhanced antitumor efficacy of adoptive cell therapy and PD-1 blockade. In established murine breast, lung, and melanoma tumors, intratumoral, peripheral, and lymph node lymphocytes were positive for senescence-associated beta-galactosidase. While induced Tregs did not cause apoptosis or cell death, co-culture of CD4+ and CD8+ T cells with either tumor cells or induced Tregs resulted in populations of senescence-associated beta-galactosidase-positive cells as well as loss of lamin B1 expression. Consistent with previous studies linking the DNA damage response to senescence, lymphocytes isolated from tumor-bearing mice as well as co-cultured with tumor cells or induced Tregs had high levels of phosphorylation of ATM and its downstream targets H2AX and CHK2. Activation of MAPK signaling was also observed at high levels in T cells co-cultured with tumor cells or induced Tregs, evident as phosphorylated P38, ERK, and JNK. Pharmacologic inhibition of JNK, P38, and ERK1/2 alleviated loss of lamin B1 in senescent T cells in vitro. In mouse models of melanoma, pharmacologic inhibition of ATM or P38 alone had no effect on tumor growth. However, inhibition of ATM or P38 potentiated the anti-tumor effects of adoptive cell therapy, with even further inhibition of tumor growth as well as prolonged survival observed when anti-PD-1 was added. The findings reveal new insight into the myriad pathways underlying immune dysfunction in the tumor microenvironment, supporting further investigation of combination approaches targeting the DNA damage response or MAPK signaling with checkpoint inhibition.
Lieke L van der Woude, Mark A J Gorris, Inge M N Wortel, Jeroen H A Creemers, Kiek Verrijp, Kim Monkhorst, Katrien Grünberg, Michel M van den Heuvel, Johannes Textor, Carl G Figdor, Berber Piet, Willemijn S M E Theelen, I Jolanda M de Vries
Journal for ImmunoTherapy of Cancer 2022;10:e005433 (17 October 2022)
RESEARCH
Summary:
PEMBRO-RT was a randomized, phase II trial in which the addition of stereotactic body radiotherapy (SBRT) directed against a single lesion increased the overall response rate to pembrolizumab from 18% to 36% in patients with advanced non-small cell lung cancer. Reporting on treatment-associated changes in the tumor microenvironment in patients enrolled in PEMBRO-RT, Lieke L van der Woude and colleagues provide evidence that SBRT in combination with checkpoint blockade leads to enhanced T cell infiltration in both irradiated and non-irradiated lesions. Expectedly, both pembrolizumab alone and pembrolizumab in combination with SBRT resulted in significant increases in the total numbers of tumor-infiltrating lymphocytes after 6 weeks on treatment. Higher numbers of tumor-infiltrating lymphocytes at baseline was associated with response across both treatment groups. While total lymphocytic infiltration in non-irradiated sites increased post-treatment for both the pembrolizumab alone and the pembrolizumab plus SBRT groups, the fold change in intratumoral CD103+ cytotoxic T cells was roughly twice as high for the combination. The study establishes evidence that locally directed radiation in combination with checkpoint blockade can induce meaningful immunologic changes in distal lesions, consistent with an abscopal effect.
Carsten Krieg, Lukas M Weber, Bruno Fosso, Marinella Marzano, Gary Hardiman, Monica M Olcina, Enric Domingo, Sahar El Aidy, Khalil Mallah, Mark D Robinson, Silvia Guglietta
Journal for ImmunoTherapy of Cancer 2022;10:e004717 (22 September 2022)
RESEARCH
Summary:
Toll-like receptor 7 (TLR7) agonism activates antigen-presenting cells resulting in T cell activation as well as intratumoral infiltration of natural killer cells and tumor antigen-specific interferon-secreting effector cells. Xiaolu Yu and colleagues demonstrate potent anti-tumor activity in multiple pre-clinical models for a novel PD-L1-directed nanobody coupled to a TLR7 agonist. In murine CT26 colon cancer models, treatment with the nanobody-TLR7 agonist conjugate impaired tumor growth for both early and established tumors, with mice that achieved complete regressions rejecting rechallenge for more than 40 days. Immunophenotyping revealed maturation of dendritic cells, repolarization of tumor-associated macrophages and increased PD-L1 expression on macrophages upon treatment with the nanobody-TLR7 agonist conjugate. Strikingly, although treatment with the nanobody conjugate resulted in upregulation of PD-L1 on tumor cells and intratumoral leukocytes, expression on peripheral blood and spleen cells was downregulated as dosing progressed. Host PD-L1 was required for tumor control, but knockout of PD-L1 in tumor cells did not impair efficacy nor upregulation of PD-L1 on intratumoral macrophages with treatment. Safety evaluations revealed no evidence of pathological damage to organs of concern nor abnormalities in hematology or plasma chemistry parameters. This preclinical evidence highlights the potential of nanobodies as a platform technology for directly targeting immune exhaustion within the tumor microenvironment while simultaneously enhancing T cell infiltration to immunologically cold tumors via delivery of innate immune agonists.
Niklas Kehl, Michael Kilian, Julius Michel, Tim R Wagner, Sebastian Uhrig, Alexander Brobeil, Lilli-Sophie Sester, Sven Blobner, Simon Steiger, Michael Hundemer, Niels Weinhold, Karsten Rippe, Stefan Fröhling, Stefan B Eichmüller, Lukas Bunse, Carsten Müller-Tidow, Hartmut Goldschmidt, Michael Platten, Marc-Steffen Raab, Mirco J Friedrich
Journal for ImmunoTherapy of Cancer 2022;10:e004590 (17 October 2022)
SHORT REPORT
Summary:
IgE type multiple myeloma is a highly aggressive and rare subtype of the plasma cell malignancy that is associated with a very poor prognosis. Integrating DNA and single cell-RNA sequencing, Niklas Kehl and colleagues describe the first comprehensive genomic and immune profiling of IgE multiple myeloma. A male patient in his late 30s with standard risk cytogenetics and multiple osteolytic bone lesions received initial treatment with four cycles of bortezomib, cyclophosphamide, and dexamethasone, followed by tandem high dose melphalan therapy and autologous stem cell transplantation and lenalidomide/dexamethasone maintenance and had a best response of stable disease with early relapse 12 months after completion of therapy. IgE type multiple myeloma cells from bone marrow aspirates displayed a distinct transcriptional profile compared to published datasets from non-IgE type myeloma cells. Although the overall abundance of individual subsets of tumor-infiltrating lymphocytes did not differ between this case of IgE type multiple myeloma and the comparison cohort of non-IgE type myelomas, a hyperexpanded T cell repertoire of effector and cytotoxic T cells was identified. Strikingly, this case of IgE type multiple myeloma had the highest tumor mutation burden of multiple myeloma genomes analyzed, with 5.0 non-synonymous mutations per coding megabase. Among the 124 peptides identified as potential neoepitopes via haplotyping, somatic variant calling, and MHC class I binding prediction, four motifs were identified that elicited T cell cytokine responses in vitro, of which two were identified as highly expressed in IgE type multiple myeloma. Although the generalizability of this single case may be limited, these data emphasize the value of next-generation sequencing techniques to provide potentially actionable therapeutic insights for rare diseases and provide a conceptual foundation for future exploration of personalized adoptive cell therapy approaches.