Recent advances in our understanding of the dynamics of cellular cross-talk have highlighted the significance of host-versus-tumor effect that can be harnessed with immune therapies. Tumors exploit immune checkpoints to evade adaptive immune responses. Cancer immunotherapy has witnessed a revolution in the past decade with the development of immune checkpoint inhibitors (ICIs), monoclonal antibodies against cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or their ligands, such as PD1 ligand 1 (PD-L1). ICIs have been reported to have activity against a broad range of tumor types, in both solid organ and hematologic malignancy contexts. However, less than one-third of the patients achieve a durable and meaningful treatment response. Expression of immune checkpoint ligands (e.g., PD-L1), mutational burden and tumor-infiltrating lymphocytes are currently used as biomarkers for predicting response to ICIs. However, they do not reliably predict which patients will benefit from these therapies. There is dire need to discover novel biomarkers to predict treatment efficacy and to identify areas for development of combination strategies to improve response rates. Emerging evidence suggests key roles of tumor extracellular matrix (ECM) components and their proteolytic remodeling products in regulating each step of the cancer-immunity cycle. Here we review tumor matrix dynamics and matrix remodeling in context of anti-tumor immune responses and immunotherapy and propose the exploration of matrix-based biomarkers to identify candidates for immune therapy.

Colorectal cancer (CRC) originates within immunologically complex microenvironments. To date the benefits of immunotherapy have been modest except in neoantigen-laden mismatch repair (MMR)-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes in the tumor bed may substantially augment clinical immunotherapy responses. Here we report that proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) strongly correlated with CD8+ T-cell infiltration in CRC, regardless of mismatch-repair status. Tumors displaying active VCAN proteolysis and low total VCAN were associated with robust (10-fold) CD8+ T-cell infiltration. Tumor-intrinsic WNT pathway activation was associated with CD8+ T-cell exclusion and VCAN accumulation. In addition to regulating VCAN levels at the tumor site, VCAN proteolysis results in the generation of bioactive fragments with novel functions (VCAN-derived matrikines). The VCAN-derived matrikine, versikine, enhanced the generation of CD103+CD11chiMHCIIhi conventional dendritic cells (cDC) (homologous to Batf3-DC/CD8α+ DC/CD103+ DC/cDC1 subset/intratumoral DC2) from Flt3L-mobilized primary bone marrow-derived progenitors, suggesting that VCAN proteolysis may promote differentiation of tumor-seeding DC precursors towards IRF8- and BATF3-expressing cDC. Intratumoral BATF3-dependent DC are critical determinants for T-cell anti-tumor immunity, effector T cell trafficking to the tumor site and response to immunotherapies. Our findings provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker and VCAN-derived matrikines as novel immunotherapy agents.

NRAS Q61 mutations are prevalent in advanced/relapsed multiple myeloma (MM) and correlate with poor patient outcomes. Thus, we generated a novel MM model by conditionally activating expression of endogenous NrasQ61R and a MYC transgene in germinal center B cells (VQ mice). VQ mice developed a highly malignant MM characterized by high proliferation index, hyperactivation of ERK and AKT signaling, impaired hematopoiesis, widespread extramedullary disease, bone lesions, kidney abnormalities, preserved PD1 and TIGIT immune checkpoint pathways, and expression of human high-risk MM gene signatures. VQ MM mice recapitulate most of the biological and clinical features of human advanced/high-risk MM. These MM phenotypes are serially transplantable in syngeneic recipients. Two MM cell lines were also derived to facilitate future genetic manipulations. Combination therapies based on MEK inhibition significantly prolonged the survival of VQ mice with advanced stage MM. Our study provides a strong rationale to develop MEK inhibition-based therapies for treating advanced/relapsed MM.

The last 10-15 years have witnessed a revolution in treating multiple myeloma, an incurable cancer of Ab-producing plasma cells. Advances in myeloma therapy were ushered in by novel agents that remodel the myeloma immune microenvironment. The first generation of novel agents included immunomodulatory drugs (thalidomide analogs) and proteasome inhibitors that target crucial pathways that regulate immunity and inflammation, such as NF-κB. This paradigm continued with the recent regulatory approval of mAbs (elotuzumab, daratumumab) that impact both tumor cells and associated immune cells. Moreover, recent clinical data support checkpoint inhibition immunotherapy in myeloma. With the success of these agents has come the growing realization that the myeloid infiltrate in myeloma lesions-what we collectively call the myeloid-in-myeloma compartment-variably sustains or deters tumor cells by shaping the inflammatory milieu of the myeloma niche and by promoting or antagonizing immune-modulating therapies. The myeloid-in-myeloma compartment includes myeloma-associated macrophages and granulocytes, dendritic cells, and myeloid-derived-suppressor cells. These cell types reflect variable states of differentiation and activation of tumor-infiltrating cells derived from resident myeloid progenitors in the bone marrow-the canonical myeloma niche-or myeloid cells that seed both canonical and extramedullary, noncanonical niches. Myeloma-infiltrating myeloid cells engage in crosstalk with extracellular matrix components, stromal cells, and tumor cells. This complex regulation determines the composition, activation state, and maturation of the myeloid-in-myeloma compartment as well as the balance between immunogenic and tolerogenic inflammation in the niche. Redressing this balance may be a crucial determinant for the success of antimyeloma immunotherapies.