Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer.

The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.

Dendritic cells in the tumor microenvironment: prognostic and theranostic impact.

Among all immune cells, dendritic cells (DC) are the most potent APCs in the immune system and are central players of the adaptive immune response. There are phenotypically and functionally distinct DC populations derived from blood and lymphoid organ including plasmacytoid DC (pDC), conventional DC (cDC1 and cDC2) and monocyte-derived DC (moDC). The interaction between these different DCs and tumors is a dynamic process where DC-mediated cross-priming of tumor specific T cells is critical in initiating and sustaining anti-tumor immunity. Their presence within the tumor tends to induce T cell responses and to reduce cancer progression and is associated with improved patient survival. This review will focus on the distinct tumor-associated DCs (TADC) subsets in the tumor microenvironment (TME), their roles in tumor immunology and their prognostic and/or predictive impact in human cancers. The development of therapeutic immunity strategies targeting TADC is promising to enhance their immune-stimulatory capacity in cancers and improve the efficacy of current immunotherapies including immune checkpoint inhibitor (ICI) blockade and DC-based therapies.

Tertiary Lymphoid Structures and B cells: Clinical impact and therapeutic modulation in cancer.

Tumors progression is under the control of a heterogeneous microenvironment composed of immune cells, fibroblasts, blood and lymphatic vessels, in which T cells have been demonstrated to be major actors, through their cytotoxic and cytokine producing effector functions and their long term memory that protects against metastasis. In this scenario, lessons from mouse models taught that B cells exert a protumoral role, via macrophage-dependent activation of inflammation. However, it became progressively evident from studies in patients with human cancers that the anti-tumor responses can be generated and controlled in tertiary lymphoid structures (TLS) that concentrate most of the intratumoral B cells and where B cells can differentiate into plasma cells and memory cells. Furthermore, recent studies demonstrated that the presence in tumors of B cells and TLS are associated with favorable outcome in patients treated by immunotherapy, unraveling TLS as a new predictive marker of anti-tumor response human cancers. This review encompasses the characteristics and functions of TLS and of B cells in human tumors, their prognostic and theranostic impact and summarizes the mouse models used to induce TLS neogenesis in tumors.

Persistence of Coxiella burnetii, the agent of Q fever, in murine adipose tissue.

Coxiella burnetii, the agent of Q fever, is known to persist in humans and rodents but its cellular reservoir in hosts remains undetermined. We hypothesized that adipose tissue serves as a C. burnetii reservoir during bacterial latency. BALB/c and C57BL/6 mice were infected with C. burnetii by the intraperitoneal route or the intracheal route. Adipose tissue was tested for the presence of C. burnetii several months after infection. C. burnetii was detected in abdominal, inguinal and dorsal adipose tissue 4 months post-infection, when no bacteria were detected in blood, liver, lungs and spleen, regardless of the inoculation route and independently of mouse strain. The transfer of abdominal adipose tissue from convalescent BALB/c mice to naïve immunodeficient mice resulted in the infection of the recipient animals. It is likely that C. burnetii infects adipocytes in vivo because bacteria were found in adipocytes within adipose tissue and replicated within in vitro-differentiated adipocytes. In addition, C. burnetii induced a specific transcriptional program in in-vivo and in vitro-differentiated adipocytes, which was enriched in categories associated with inflammatory response, hormone response and cytoskeleton. These changes may account for bacterial replication in in-vitro and chronic infection in-vivo. Adipose tissue may be the reservoir in which C. burnetii persists for prolonged periods after apparent clinical cure. The mouse model of C. burnetii infection may be used to understand the relapses of Q fever and provide new perspectives to the follow-up of patients.