8 research outputs found
Loss-of-function alleles of P2RX7 and TLR4 fail to affect the response to chemotherapy in non-small cell lung cancer
The success of anticancer chemotherapy relies at least in part on the induction of an immune response against tumor cells. Thus, tumors growing on mice that lack the pattern recognition receptor TLR4 or the purinergic receptor P2RX7 fail to respond to chemotherapy with anthracyclins or oxaliplatin in conditions in which the same neoplasms growing on immunocompetent mice would do so. Similarly, the therapeutic efficacy (measured as progression-free survival) of adjuvant chemotherapy with anthracyclins is reduced in breast cancer patients bearing loss-of-function alleles of TLR4 or P2RX7. TLR4 loss-of-function alleles also have a negative impact on the therapeutic outcome of oxaliplatin in colorectal cancer patients. Here, we report that loss-of-function TLR4 and P2RX7 alleles do not affect overall survival in non-small cell lung cancer (NSCLC) patients, irrespective of the administration and type of chemotherapy. The intrinsic characteristics of NSCLC (which near-to-always is chemoresistant and associated with poor prognosis) and/or the type of therapy that is employed to treat this malignancy (which near-to-always is based on cisplatin) may explain why two genes that affect the immune response to dying cells fail to influence the clinical progression of NSCLC patients
Consensus guidelines for the detection of immunogenic cell death
none82siApoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.Kepp, Oliver; Senovilla, Laura; Vitale, Ilio; Vacchelli, Erika; Adjemian, Sandy; Agostinis, Patrizia; Apetoh, Lionel; Aranda, Fernando; Barnaba, Vincenzo; Bloy, Norma; Bracci, Laura; Breckpot, Karine; Brough, David; BuquĂ©, Aitziber; Castro, Maria G; Cirone, Mara; Colombo, Maria I; Cremer, Isabelle; Demaria, Sandra; Dini, Luciana; Eliopoulos, Aristides G; Faggioni, Alberto; Formenti, Silvia C; FuÄĂkovĂĄ, Jitka; Gabriele, Lucia; Gaipl, Udo S; Galon, JĂ©rĂŽme; Garg, Abhishek; Ghiringhelli, François; Giese, Nathalia A; Guo, Zong Sheng; Hemminki, Akseli; Herrmann, Martin; Hodge, James W; Holdenrieder, Stefan; Honeychurch, Jamie; Hu, Hong-Min; Huang, Xing; Illidge, Tim M; Kono, Koji; Korbelik, Mladen; Krysko, Dmitri V; Loi, Sherene; Lowenstein, Pedro R; Lugli, Enrico; Ma, Yuting; Madeo, Frank; Manfredi, Angelo A; Martins, Isabelle; Mavilio, Domenico; Menger, Laurie; Merendino, NicolĂČ; Michaud, Michael; Mignot, Gregoire; Mossman, Karen L; Multhoff, Gabriele; Oehler, Rudolf; Palombo, Fabio; Panaretakis, Theocharis; Pol, Jonathan; Proietti, Enrico; Ricci, Jean-Ehrland; Riganti, Chiara; Rovere-Querini, Patrizia; Rubartelli, Anna; Sistigu, Antonella; Smyth, Mark J; Sonnemann, Juergen; Spisek, Radek; Stagg, John; Sukkurwala, Abdul Qader; Tartour, Eric; Thorburn, Andrew; Thorne, Stephen H; Vandenabeele, Peter; Velotti, Francesca; Workenhe, Samuel T; Yang, Haining; Zong, Wei-Xing; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, LorenzoKepp, Oliver; Senovilla, Laura; Vitale, Ilio; Vacchelli, Erika; Adjemian, Sandy; Agostinis, Patrizia; Apetoh, Lionel; Aranda, Fernando; Barnaba, Vincenzo; Bloy, Norma; Bracci, Laura; Breckpot, Karine; Brough, David; BuquĂ©, Aitziber; Castro, Maria G; Cirone, Mara; Colombo, Maria I; Cremer, Isabelle; Demaria, Sandra; Dini, Luciana; Eliopoulos, Aristides G; Faggioni, Alberto; Formenti, Silvia C; FuÄĂkovĂĄ, Jitka; Gabriele, Lucia; Gaipl, Udo S; Galon, JĂ©rĂŽme; Garg, Abhishek; Ghiringhelli, François; Giese, Nathalia A; Guo, Zong Sheng; Hemminki, Akseli; Herrmann, Martin; Hodge, James W; Holdenrieder, Stefan; Honeychurch, Jamie; Hu, Hong Min; Huang, Xing; Illidge, Tim M; Kono, Koji; Korbelik, Mladen; Krysko, Dmitri V; Loi, Sherene; Lowenstein, Pedro R; Lugli, Enrico; Ma, Yuting; Madeo, Frank; Manfredi, Angelo A; Martins, Isabelle; Mavilio, Domenico; Menger, Laurie; Merendino, NicolĂČ; Michaud, Michael; Mignot, Gregoire; Mossman, Karen L; Multhoff, Gabriele; Oehler, Rudolf; Palombo, Fabio; Panaretakis, Theocharis; Pol, Jonathan; Proietti, Enrico; Ricci, Jean Ehrland; Riganti, Chiara; Rovere Querini, Patrizia; Rubartelli, Anna; Sistigu, Antonella; Smyth, Mark J; Sonnemann, Juergen; Spisek, Radek; Stagg, John; Sukkurwala, Abdul Qader; Tartour, Eric; Thorburn, Andrew; Thorne, Stephen H; Vandenabeele, Peter; Velotti, Francesca; Workenhe, Samuel T; Yang, Haining; Zong, Wei Xing; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenz
Lâautophagie : Un nouveau modulateur de la mort cellulaire immunogĂšne dans le traitement des cancers
Certains agents chimiothĂ©rapeutiques tels que les anthracyclines ou l'oxaliplatine induisent une mort cellulaire immunogĂšne, ce qui implique que les cellules mourrantes du patient servent de vaccin thĂ©rapeutique en stimulant une rĂ©ponse immunitaire antitumorale. La mort cellulaire immunogĂšne est caractĂ©risĂ©e par la libĂ©ration de signaux d'alarme par la cellule tumorale mourante qui permettent lâactivation du systĂšme immunitaire. En premier lieu, l'exposition de la calrĂ©ticuline Ă la surface de la cellule tumorale mourante va agir comme un signal de type «eat-me» pour les cellules dendritiques. Une fois relĂąchĂ©e, la protĂ©ine nuclĂ©aire HMGB1 se lie au rĂ©cepteur TLR4 afin de faciliter la prĂ©sentation antigĂ©nique. Les cellules mourantes vont Ă©galement libĂ©rer de l'ATP qui agit sur les rĂ©cepteurs P2X7 et active lâinflammasomme NLRP3, conduisant Ă la libĂ©ration d'IL-1ÎČ et ainsi Ă lâactivation des cellules T CD8+ productrices dâIFN-Îł. Lâautophagie est un mĂ©canisme cellulaire qui est activĂ© en rĂ©ponse Ă la chimiothĂ©rapie. L'autophagie signifie «self-ating», il s'agit d'un processus cellulaire activĂ© par diverses conditions de stress, par lequel les cellules peuvent dĂ©grader les protĂ©ines et les organites. Il peut aussi ĂȘtre induit par un stress du rĂ©ticulum endoplasmique. Ce dernier Ă©tant Ă©galement impliquĂ© dans l'exposition de la calrĂ©ticuline pendant la mort cellulaire immunogĂšne, nous avons au cours de cette Ă©tude cherchĂ© Ă dĂ©terminer le rĂŽle de l'autophagie dans la mort cellulaire immunogĂšne. Nous avons constatĂ© que l'autophagie est nĂ©cessaire pour la libĂ©ration de l'ATP aprĂšs un traitement par des chimiothĂ©rapies immunogĂšnes, en observant que le nockdown de gĂšnes essentiels de l'autophagie limitait la sĂ©crĂ©tion d'ATP. Nous avons Ă©galement observĂ© que des cellules dĂ©ficientes pour l'autophagie traitĂ©es par une chimiothĂ©rapie immunogĂšne sont incapables dâimmuniser des souris contre une injection de cellules vivantes. En outre, les tumeurs dĂ©ficientes pour lâautophagie ne rĂ©pondent pas Ă un traitement systĂ©mique immunogĂšne dans des souris immunocompĂ©tentes et continuent Ă prolifĂ©rer en comparaison Ă des tumeurs âwild-typeâ. De plus, nous avons montrĂ© que les cellules dĂ©ficientes pour l'autophagie ne sont pas en mesure de recruter des cellules dendritiques dans le lit tumoral ou d'induire lâactivation des cellules T CD8+. A l'inverse, l'inhibition des enzymes de dĂ©gradation de lâATP extracellulaire accroit les concentrations d'ATP dans les tumeurs dĂ©ficientes pour l'autophagie, ce qui rĂ©tablit le recrutement des cellules immunitaires dans le lit tumoral et restaure la rĂ©ponse chimiothĂ©rapeutique des cancers dĂ©ficients pour l'autophagie. Ainsi, cette Ă©tude a montrĂ© l'importance de l'autophagie dans la rĂ©ponse anti-tumorale spĂ©cifique, aprĂšs traitement par des chimiothĂ©rapies immunogĂšnes. Ces rĂ©sultats ouvrent de nouvelles perspectives dans le concept de la mort cellulaire immunogĂšne.In recent years it has been demonstrated that some chemotherapeutic agents such as anthracyclines or oxaliplatin can induce a type of tumor cell death that is immunogenic, implying that the patientâs dying cancer cells serve as a therapeuticvaccine that stimulates an antitumor immune response, which in turn can control or eradicate residual cancer cells. Immunogenic cell death is characterized by the emission of danger signals from the dying tumor cell, which activate the immune system. At first the exposure of calreticulin, acts as an «eat-me» signal for dendritic cells (DCs). Once released, the nuclear protein HMGB1 binds to TLR4 on DCs, facilitating antigen processing and presentation. The dying tumor cells also releases ATP, which acts on P2X7 receptors on DCs and activates the NLRP3 inflammasome, leading to IL-1ÎČ release, necessary for IFN-Îł-producing CD8+ T cell activation. Autophagy literally âself-eatingâ is a cellular process activated in response to various conditions of cellular stress, whereby cells can liberate energy resources via the degradation of proteins and organelles. Recently autophagy has been found activated in response to chemotherapy and in this project we aimed to determine the potential role of autophagy in immunogenic cell death. We found that autophagy isrequired for the release of ATP in response to immunochemotherapeutic treatment, as we observed that the knockdown of essential autophagy-related genes abolished its secretion. We observed that autophagy deficient cells treated with immunogenic cell death inducers failed to immunize mice against a re-challenge with living cells. Furthermore, autophagy deficient tumors growing on immunocompetent mice did not respond to systemic immunogenic treatment and continued proliferating in contrast to autophagy proficient tumors. We showed that autophagy deficient cells were neither able to recruit DCs into the tumor bed nor to activate CD8+ T cells. Conversely, the inhibition of extracellular ATP degrading enzymes increased extracellular ATP concentrations in autophagy deficient tumors, which reestablished the recruitment of immune cells into the tumor bed, and restored chemotherapeutic responses in autophagy-deficient cancers. Altogether, this study showed the importance of autophagy in tumor-specific immune response after treatment with chemotherapy, thus giving new insights into the concept of immunogenic cell death
ATP-dependent recruitment, survival and differentiation of dendritic cell precursors in the tumor bed after anticancer chemotherapy
International audienceTumor cells succumb to chemotherapy while releasing ATP. We have found that extracellular ATP attracts dendritic cell (DC) precursors into the tumor bed, facilitates their permanence in the proximity of dying cells and promotes their differentiation into mature DCs endowed with the capacity of presenting tumor-associated antigens
EGFR inhibitors exacerbate differentiation and cell cycle arrest induced by retinoic acid and vitamin D 3
Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells
The therapeutic efficacy of anthracyclines relies on antitumor immune responses elicited by dying cancer cells. How chemotherapy-induced cell death leads to efficient antigen presentation to T cells, however, remains a conundrum. We found that intratumoral CD11c+CD11b+Ly6Chi cells, which displayed some characteristics of inflammatory dendritic cells and included granulomonocytic precursors, were crucial for anthracycline-induced anticancer immune responses. ATP released by dying cancer cells recruited myeloid cells into tumors and stimulated the local differentiation of CD11c+CD11b+Ly6Chi cells. Such cells efficiently engulfed tumor antigens in situ and presented them to T lymphocytes, thus vaccinating mice, upon adoptive transfer, against a challenge with cancer cells. Manipulations preventing tumor infiltration by CD11c+CD11b+Ly6Chi cells, such as the local overexpression of ectonucleotidases, the blockade of purinergic receptors, or the neutralization of CD11b, abolished the immune system-dependent antitumor activity of anthracyclines. Our results identify a subset of tumor-infiltrating leukocytes as therapy-relevant antigen-presenting cells
Consensus guidelines for the detection of immunogenic cell death
Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine