Abstract The link between cancer metabolism and immunosuppression, inflammation and immune escape has generated major interest in investigating the effects of low pH on tumor immunity. Indeed, ...microenvironmental acidity may differentially impact on diverse components of tumor immune surveillance, eventually contributing to immune escape and cancer progression. Although the molecular pathways underlying acidity-related immune dysfunctions are just emerging, initial evidence indicates that antitumor effectors such as T and NK cells tend to lose their function and undergo a state of mostly reversible anergy followed by apoptosis, when exposed to low pH environment. At opposite, immunosuppressive components such as myeloid cells and regulatory T cells are engaged by tumor acidity to sustain tumor growth while blocking antitumor immune responses. Local acidity could also profoundly influence bioactivity and distribution of antibodies, thus potentially interfering with the clinical efficacy of therapeutic antibodies including immune checkpoint inhibitors. Hence tumor acidity is a central regulator of cancer immunity that orchestrates both local and systemic immunosuppression and that may offer a broad panel of therapeutic targets. This review outlines the fundamental pathways of acidity-driven immune dysfunctions and sheds light on the potential strategies that could be envisaged to potentiate immune-mediated tumor control in cancer patients.
Hyperprogression (HP), a paradoxical boost in tumor growth, was described in a subset of patients treated with immune checkpoint inhibitors (ICI). Neither clinicopathologic features nor biological ...mechanisms associated with HP have been identified.
Among 187 patients with non-small cell lung cancer (NSCLC) treated with ICI at our institute, cases with HP were identified according to clinical and radiologic criteria. Baseline histologic samples from patients treated with ICI were evaluated by IHC for myeloid and lymphoid markers. T-cell-deficient mice, injected with human lung cancer cells and patient-derived xenografts (PDX) belonging to specific mutational subsets, were assessed for tumor growth after treatment with antibodies against mouse and human programmed death receptor-1 (PD-1). The immune microenvironment was evaluated by flow cytometry and IHC.
Among 187 patients, 152 were evaluable for clinical response. We identified four categories: 32 cases were defined as responders (21%), 42 patients with stable disease (27.7%), 39 cases were defined as progressors (25.7%), and 39 patients with HP (25.7%). Pretreatment tissue samples from all patients with HP showed tumor infiltration by M2-like CD163
CD33
PD-L1
clustered epithelioid macrophages. Enrichment by tumor-associated macrophages (TAM) was observed, even in tumor nodules from immunodeficient mice injected with human lung cancer cells and with PDXs. In these models, tumor growth was enhanced by treatment with anti-PD-1 but not anti-PD-1 F(ab)
fragments.
These results suggest a crucial role of TAM reprogramming, upon Fc receptor engagement by ICI, eventually inducing HP and provide clues on a distinctive immunophenotype potentially able to predict HP.
.
Natural killer (NK) cells contribute to immunosurveillance and first-line defense in the control of tumor growth and metastasis diffusion. NK-cell-derived extracellular vesicles (NKEVs) are ...constitutively secreted and biologically active. They reflect the protein and genetic repertoire of originating cells, and exert antitumor activity
and
. Cancer can compromise NK cell functions, a status potentially reflected by their extracellular vesicles. Hence, NKEVs could, on the one hand, contribute to improve cancer therapy by interacting with tumor and/or immune cells and on the other hand, sense the actual NK cell status in cancer patients. Here, we investigated the composition of healthy donors' NKEVs, including NK microvesicles and exosomes, and their interaction with uncompromised cells of the immune system. To sense the systemic NK cell status in cancer patients, we developed an immune enzymatic test (NKExoELISA) that measures plasma NK-cell-derived exosomes, captured as tsg101
CD56
nanovesicles. NKEV mass spectrometry and cytokine analysis showed the expression of NK cell markers, i.e., NKG2D and CD94, perforin, granzymes, CD40L, and other molecules involved in cytotoxicity, homing, cell adhesion, and immune activation, together with EV markers tsg101, CD81, CD63, and CD9 in both NK-derived exosomes and microvesicles. Data are available via Proteome Xchange with identifier PXD014894. Immunomodulation studies revealed that NKEVs displayed main stimulatory functions in peripheral blood mononuclear cells (PBMCs), inducing the expression of human leukocyte antigen DR isotype (HLA-DR) and costimulatory molecules on monocytes and CD25 expression on T cells, which was maintained in the presence of lipopolysaccharide (LPS) and interleukin (IL)-10/transforming growth factor beta (TGFβ), respectively. Furthermore, NKEVs increased the CD56
NK cell fraction, suggesting that effects mediated by NKEVs might be potentially exploited in support of cancer therapy. The measurement of circulating NK exosomes in the plasma of melanoma patients and healthy donors evidenced lower levels of tsg101
CD56
exosomes in patients with respect to donors. Likewise, we detected lower frequencies of NK cells in PBMCs of these patients. These data highlight the potential of NKExoELISA to sense alterations of the NK cell immune status.
It has been for long conceived that hallmarks of cancer were intrinsic genetic features driving tumor development, proliferation, and progression, and that targeting such cell-autonomous pathways ...could be sufficient to achieve therapeutic cancer control. Clinical ex vivo data demonstrated that treatment efficacy often relied on the contribution of host immune responses, hence introducing the concept of tumor microenvironment (TME), namely the existence, along with tumor cells, of non-tumor components that could significantly influence tumor growth and survival. Among the complex network of TME-driving forces, immunity plays a key role and the balance between antitumor and protumor immune responses is a major driver in contrasting or promoting cancer spreading. TME is usually a very immunosuppressed milieu because of a vast array of local alterations contrasting antitumor adaptive immunity, where metabolic changes contribute to cancer dissemination by impairing T cell infiltration and favoring the accrual and activation of regulatory cells. Subcellular structures known as extracellular vesicles then help spreading immunosuppression at systemic levels by distributing genetic and protein tumor repertoire in distant tissues. A major improvement in the knowledge of TME is now pointing the attention back to tumor cells; indeed, recent findings are showing how oncogenic pathways and specific mutations in tumor cells can actually dictate the nature and the function of immune infiltrate. As our information on the reciprocal interactions regulating TME increases, finding a strategy to interfere with TME crosstalk becomes more complex and challenging. Nevertheless, TME interactions represent a promising field for the discovery of novel biomarkers and therapeutic targets for improving treatment efficacy in cancer.
The onset of cancer is unavoidably accompanied by suppression of antitumor immunity. This occurs through mechanisms ranging from the progressive accumulation of regulatory immune cells associated ...with chronic immune stimulation and inflammation, to the expression of immunosuppressive molecules. Some of them are being successfully exploited as therapeutic targets, with impressive clinical results achieved in patients, as in the case of immune checkpoint inhibitors. To limit immune attack, tumor cells exploit specific pathways to render the tumor microenvironment hostile for antitumor effector cells. Local acidification might, in fact, anergize activated T cells and facilitate the accumulation of immune suppressive cells. Moreover, the release of extracellular vesicles by tumor cells can condition distant immune sites contributing to the onset of systemic immune suppression. Understanding which mechanisms may be prevalent in specific cancers or disease stages, and identifying possible strategies to counterbalance would majorly contribute to improving clinical efficacy of cancer immunotherapy. Here, we intend to highlight these mechanisms, how they could be targeted and the tools that might be available in the near future to achieve this goal.
If immunotherapy is currently considered as a valid treatment strategy in oncology, the concept that cancer could be cured by the mere manipulation of the immune system was almost inconceivable until ...few years ago, particularly in lung cancer. The use of immune checkpoint inhibitors has instead demonstrated to mediate significant long-term disease control so to rapidly enter clinical practice and represent the basis for most of the combination approaches under development. In light of the revolutionary results achieved through the pivotal clinical trials and the large expectations about the possibility to further improve clinical benefit and discover novel therapeutic targets, it is becoming nowadays mandatory to increase our knowledge on the basics of immunology in lung cancer. Defining the pathways that rule the interactions between tumor and immune cells and the requirements to achieve full-fledged immune responses able to mediate meaningful antitumor activity are present goals of the research ongoing worldwide. This knowledge would not only foster a more scientifically-based clinical development of novel drugs and combinations, but also provide valid biomarkers for patient selection and monitoring. In the present review we will address the available information about the immunological features of lung cancer, the backgrounds to the use of immunotherapeutics, the possible mechanisms underlying resistance and the strategies to improve immune-mediated tumor control. In doing this, we will be following the path traced in melanoma, the tumor histotype that taught us most of what we know about cancer immunotherapy.
Background: Plasma EVs, a heterogeneous population of vesicles with different origins, have attracted major interest as biomarker source, especially in cancer patients. Besides containing those ...deriving from tumour cells, the composition and phenotype of plasma EVs might reflect immune status and its modulation in relation to anti-cancer agents. Here we investigated if the EV phenotype associated with changes in routine blood tests and peripheral blood immunophenotype in metastatic renal cell cancer patients (mRCC) undergoing tyrosine kinase inhibitor (TKI) therapy. Methods: After approval by the internal ethical committee, PBMCs and plasma samples were collected from consenting patients at baseline, 3 and 6 months during therapy and stored in liquid N2 and -80°C, respectively. EVs, isolated by two-step differential centrifugation, were evaluated by flow cytometry and western blot. PBMC immunomonitoring was performed by 10-colour cytofluorimetry. Results: EVs contained in F1 (16,500 g) and F2 (118,000 g) expressed CD9 and VLA-2 and both proteins decreased in expression after 3 months TKI administration. The amount of CD9 and VLA-2 in F1 correlated significantly with a decrease of immunosuppressive CD14 +HLA-DRneg myeloid-derived suppressor cells as well as monocyte and platelet counts in samples obtained at 3 months with respect to baseline, detected by flow cytometry of PBMCs and routine blood tests. CD9 and VLA-2 in F1 EVs also correlated inversely with CD3negCD56hi16neg cells, a subset of natural killer cells. This indicates an association of circulating EV phenotype with changes occurring at peripheral blood level in RCC patients receiving TKI. Summary/Conclusion: These preliminary data suggest that plasma EVs may reflect the immune status and the immunomodulating effects occurring during cancer therapies. Additionally, they encourage the rapid development of reliable techniques for the systematic application of body fluid EVs as immune biomarkers of liquid biopsy in cancer. Funding: This work was funded by Italian Ministry of Health grant GR2011-02351400.
We present a new algorithm for the design of the connection region between different lattice materials. We solve a Stokes-type topology optimization problem on a narrow morphing region to smoothly ...connect two different unit cells. The proposed procedure turns out to be effective and provides a local re-design of the materials, leading to a very mild modification of the mechanical behavior characterizing the original lattices. The robustness of the algorithm is assessed in terms of sensitivity of the final layout to different parameters. Both the cases of Cartesian and non-Cartesian morphing regions are successfully investigated.
We propose a new algorithm to design lightweight and stiff structures exhibiting free-form features, with the aim of minimizing the compliance under a volume inequality constraint. The procedure is ...based on the coupling of geometric shape optimization with topology optimization. We start from a full-mass body corresponding to a given material occupying entirely the initial design domain. The first phase of geometric shape optimization acts as an out-of-the-box paradigm. It allows one to modify the initial design domain by acting only on its boundary, keeping the same volume and topology. With respect to the full-mass body, this phase reduces the compliance to a large extent. The successive step of topology optimization does actually change the topology of the structure, e.g., by introducing holes, reduces the volume according to the volume constraint, but does not affect the boundary of the structure, which is fixed by the previous phase. Overall, the combined approach allows us to design a new structure, that is lighter and stiffer with respect to the full-mass body. Additionally, the employment of a structure-tailored computational mesh, via an anisotropic mesh adaptation procedure during topology optimization, yields an intrinsically smooth final layout characterized by free-form features. An extensive numerical assessment corroborates both qualitatively and quantitatively the performances of the proposed optimization algorithm.
•An efficient tool for the design of 3D stiff structures exhibiting free-form features.•Geometric Shape optimization and topology optimization, separately and combined.•Structure-tailored computational mesh with anisotropic mesh adaptation yields intrinsically smooth final layouts.•Moderate robustness of the algorithm in terms of compliance – vs – volume fraction.•Preliminary algorithm with a view to a structural finite element analysis.
In this paper we focus on the thermo-mechanical model proposed in Bourdin et al. (2014) and Marigo et al. (2013) which describes crack genesis and propagation in brittle materials induced by a ...thermal shock. Our goal is to provide an efficient numerical technique which employs a computational finite element mesh finely customized to the problem at hand to simulate such phenomena in a 2D setting. In particular, we generate automatically adapted anisotropic grids able to closely follow the narrow bands of the damage, driven by a theoretically sound mathematical tool. We carry out three numerical tests to assess the computational performance of the proposed method.
•Anisotropic mesh adaptation for a one-way coupled thermo-mechanical model.•Ambrosio–Tortorelli setting plus heat equation for crack ignitation and propagation.•Anisotropic a posteriori estimator to control the error on the total energy.•Introduce MACProX algorithm, which alternates optimization and mesh adaptation.•Good performance of MACProX with respect to an isotropic mesh adaptation procedure.
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