Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16 Ink4a /p19 Arf (Cdkn2a) or p21 Cip1 (Cdkn1a) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication.

Keywords: λ-myc mouse r Endogenous B-cell lymphoma r NK-cell activation r NKG2D ligands r Tumor escape Additional supporting information may be found in the online version of this article at the publisher's web-site

Previous analyses of possible associations between MHC determinants and cutaneous malignant melanoma (MM) have been inconclusive. We have investigated 98 patients with special emphasis on histologically determined subtypes of MM, and 5 multiple-case families. In addition to HLA-ABC and DR typing, complement allotypes of C2, C4A, C4B, BF were determined. Among the unrelated patients HLA-DR5 and, secondarily, B49 were observed to be associated with superficial spreading (SSM) but not with nodular (NM) or lentigo maligna melanoma (LMM). In families with MM, no definite segregation of the disease according to HLA and complement haplotypes was discernible. Moreover, no coincidence of haplotypes occurred in patients of the different families. HLA region recombinations including B/DR and/or DR/GLO were found in all the families investigated.

Costimulatory surface molecules and instructive cytokines expressed by dendritic cells (DCs) determine the outcome of an immune response. In malignant disease, DCs are often functionally compromised. In most tumors studied so far, the deficient induction of effective T cell responses has been associated with a blockade of DC maturation, but little has been known on DCs infiltrating malignant B cell lymphoma. Here, we investigated for the first time the phenotypic and functional status of DCs in B cell lymphoma, and we analyzed the network of DCs, tumor cells, natural killer (NK) cells and cytokines present in the tumor micromilieu. Therefor, we used an endogenous myc-transgenic mouse lymphoma model, because transplanted tumor cells foster an IFN-γ-driven Th1 antitumor response rather than an immunosuppressive environment, which is observed in autochthonous neoplasias. Lymphoma-infiltrating DCs showed a mature phenotype and a Th2-inducing cytokine pattern. This situation is in contrast to most human malignancies and mouse models described. Cellular contacts between DCs and tumor cells, which involved CD62L on the lymphoma, caused upregulation of costimulatory molecules, whereas IL-10 primarily derived from lymphoma cells induced an IL-12/IL-10 shift in DCs. Thus, alteration of costimulatory molecules and instructive cytokines was mediated by distinct mechanisms. Normal NK cells were able to additionally modulate DC maturation but this effect was absent in the lymphoma environment where IFN-γ production by NK cells was severely impaired. These data are relevant for establishing novel immunotherapeutic approaches against B cell lymphoma.

It is well established that an interplay between natural killer (NK) cells and dendritic cells (DCs) gives rise to their reciprocal activation and provides a Th1-biased cytokine milieu that fosters antitumor T-cell responses. Ex vivo-differentiated DCs transferred into mice strongly stimulate endogenous NK cells to produce interferon (IFN)-c and initiate a cascade that eventually leads to cytotoxic T-lymphocyte responses. We show that the ability of exogenous DCs to trigger this pathway obviates CD40 signaling and CD41 T-cell help and depends on a preceding maturation step. Importantly, this mechanism was also effective in endogenously arising tumors where IFN-c production is compromised in contrast to transplantable tumors. In c-myc-transgenic mice developing spontaneous lymphomas, injection of unpulsed DCs caused NK-cell activation and induced CD8 1 T cells capable of recognizing the lymphoma cells. Animals treated with unpulsed DCs showed a survival benefit compared to untreated myc mice. Hence, tumor immunity induced by DC-based vaccines not only depends on specific antigens loaded on the DCs. Rather, DC vaccines generate broader immune responses, because endogenous DCs presenting tumor antigens may also become stimulated by NK cells that were activated by exogenous DCs. Thus, the DC/NK-cell/cytotoxic T lymphocyte axis may commonly have relevance for DC-based vaccination protocols in clinical settings.