Acquired resistance to anti-PD1 therapy: checkmate to checkpoint blockade?

Editorial summary Anti-programmed cell death 1 (PD1) immunotherapies are among the most effective anti-cancer immunotherapies available; however, a large number of patients present with or develop resistance to them. Unfortunately, very little is known regarding the mechanisms of resistance to such therapies. A recent study sought to identify mutations associated with resistance to anti-PD1 therapy. Results from this study demonstrated that mutations which affected the sensitivity of tumor cells to T-cell-derived interferons, and mutations limiting tumor-cell antigen presentation, could cause acquired resistance. These findings have significant implications for understanding the mechanisms by which anti-PD1 therapies exert their efficacy, comprehending why and how some patients acquire resistance over time, and ultimately guiding the development of combination therapies designed to overcome, or potentially prevent, the development of acquired immunotherapeutic resistance

From mice to humans: Developments in cancer immunoediting

Cancer immunoediting explains the dual role by which the immune system can both suppress and/or promote tumor growth. Although cancer immunoediting was first demonstrated using mouse models of cancer, strong evidence that it occurs in human cancers is now accumulating. In particular, the importance of CD8+ T cells in cancer immunoediting has been shown, and more broadly in those tumors with an adaptive immune resistance phenotype. This Review describes the characteristics of the adaptive immune resistance tumor microenvironment and discusses data obtained in mouse and human settings. The role of other immune cells and factors influencing the effector function of tumor-specific CD8+ T cells is covered. We also discuss the temporal occurrence of cancer immunoediting in metastases and whether it differs from immunoediting in the primary tumor of origin

PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux

Cancer therapies will increasingly be utilized in combination to treat advanced malignancies so as to increase their long-term efficacy in a greater proportion of patients. In particular, much attention has focused on developing targeted therapies that inhibit the PI3K-AKT-mTOR signaling network which is dysregulated in many cancer types. In addition, there is now a growing appreciation that targeting of these pathways can impact not only on cancer cells, but also host immunity. The clinical success of cancer immunotherapies targeting T-cell immune checkpoint receptors PD-1/PD-L1 has demonstrated the importance of immunoevasion as a hallmark of cancer. In this review, we discuss how PI3K-AKT-mTOR inhibitors target cancer cell biology, attenuate immune cell effector function and modulate the tumor microenvironment. We next discuss how the immunomodulatory potential of these inhibitors can be exploited through rational combinations with immunotherapies and targeted therapies

TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer

T-cell immunoglobulin mucin 3 (TIM3) is an inhibitory molecule that has emerged as a key regulator of dysfunctional or exhausted CD8+ T cells arising in chronic diseases such as cancer. In addition to exhausted CD8+ T cells, highly suppressive regulatory T cells (Tregs) represent a significant barrier against the induction of antitumor immunity. We have found that the majority of intratumoral FOXP3+ Tregs express TIM3. TIM3+ Tregs co-express PD-1, are highly suppressive and comprise a specialized subset of tissue Tregs that are rarely observed in the peripheral tissues or blood of tumor-bearing mice. The co-blockade of the TIM3 and PD-1 signaling pathways in vivo results in the downregulation of molecules associated with TIM3+ Treg suppressor functions. This suggests that the potent clinical efficacy of co-blocking TIM3 and PD-1 signal transduction cascades likely stems from the reversal of T-cell exhaustion combined with the inhibition of regulatory T-cell function in tumor tissues. Interestingly, we find that TIM3+ Tregs accumulate in the tumor tissue prior to the appearance of exhausted CD8+ T cells, and that the depletion of Tregs at this stage interferes with the development of the exhausted phenotype by CD8+ T cells. Collectively, our data indicate that TIM3 marks highly suppressive tissue-resident Tregs that play an important role in shaping the antitumor immune response in situ, increasing the value of TIM3-targeting therapeutic strategies against cancer

Measurements of the Higgs boson production and decay rates and coupling strengths using pp collision data at √S=7 and 8 TeV in the ATLAS experiment

Combined analyses of the Higgs boson production and decay rates as well as its coupling strengths to vector bosons and fermions are presented. The combinations include the results of the analyses of the H -> gamma gamma, ZZ*, WW*, Z gamma, b (b) over bar, tau tau and mu mu decay modes, and the constraints on the associated production with a pair of top quarks and on the off-shell coupling strengths of the Higgs boson. The results are based on the LHC proton-proton collision datasets, with integrated luminosities of up to 4.7 fb(-1) at root s = 7 TeV and 20.3 fb(-1) at root s = 8 TeV, recorded by the ATLAS detector in 2011 and 2012. Combining all production modes and decay channels, the measured signal yield, normalised to the Standard Model expectation, is 1.18(-0.14)(+0.15). The observed Higgs boson production and decay rates are interpreted in a leading-order coupling framework, exploring a wide range of benchmark coupling models both with and without assumptions on the Higgs boson width and on the Standard Model particle content in loop processes. The data are found to be compatible with the Standard Model expectations for a Higgs boson at a mass of 125.36 GeV for all models considered