De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors

Abstract

The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

“…67 Finally, therapeutic induction of lymphoid structures synergized with immunotherapy in mice. 68 Thus, novel combination immunotherapies may include the promotion of lymphatics despite that they are also implied in immune suppressive mechanisms and metastatic spread. Future therapy improvements may depend on the successful increase of the beneficial roles of lymphatics with simultaneous reduction of their negative effects.…”

TGF-β induced CXCL13 in CD8+ T cells is associated with tertiary lymphoid structures in cancer

“…Several novel combination immunotherapy regimes that promote CTL infiltration and TLS formation may also function via CTL-dependent production of CXCL13. For instance, combined therapy with anti-angiogenic and immunotherapeutic agents in mice stimulated the transformation of tumor blood vessels into intratumoral HEVs, which subsequently enhanced the infiltration and activation of CTLs and the destruction of tumor cells 50,51 . These CTLs formed structures around the HEVs that closely resembled TLS 50,51 .…”

“…For instance, combined therapy with anti-angiogenic and immunotherapeutic agents in mice stimulated the transformation of tumor blood vessels into intratumoral HEVs, which subsequently enhanced the infiltration and activation of CTLs and the destruction of tumor cells 50,51 . These CTLs formed structures around the HEVs that closely resembled TLS 50,51 . One of these studies found that induction of TLS was dependent on both CD8+ T cells and macrophages 50 .…”

“…These CTLs formed structures around the HEVs that closely resembled TLS 50,51 . One of these studies found that induction of TLS was dependent on both CD8+ T cells and macrophages 50 . However, the exact intratumoral mechanism of action remained unclarified.…”

Defining High Endothelial Venules and Tertiary Lymphoid Structures in Cancer

“…HEV neogenesis correlates with regression of established tumours in preclinical mouse tumour immunotherapy models, such as depletion of Foxp3 + regulatory T cells (22,23) or combined checkpoint blockade inhibition and angiogenesis therapy (24). HEV neogenesis and tumour regression are also seen when the TNF superfamily member LIGHT (TNSF14) (which signals via LTβR, an important driver of lymphoid organ development) is expressed by tumour cells or targeted to tumours or tumour blood vessels (25)(26)(27). It is thought that the antitumour effects are due to the generation of cancer cell-destroying lymphocytes from naïve T cells which have been recruited from the bloodstream into the cancer by newly formed HEV.…”