19 research outputs found
PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity
PDL1 blockade produces remarkable clinical responses,
thought to occur by T cell reactivation
through prevention of PDL1-PD1 T cell inhibitory interactions.
Here, we find that PDL1 cell-intrinsic
signaling protects cancer cells from interferon (IFN)
cytotoxicity and accelerates tumor progression.
PDL1 inhibited IFN signal transduction through a
conserved class of sequence motifs that mediate
crosstalk with IFN signaling. Abrogation of PDL1
expression or antibody-mediated PDL1 blockade
strongly sensitized cancer cells to IFN cytotoxicity
through a STAT3/caspase-7-dependent pathway.
Moreover, somatic mutations found in human carcinomas
within these PDL1 sequence motifs disrupted
motif regulation, resulting in PDL1 molecules with
enhanced protective activities from type I and type
II IFN cytotoxicity. Overall, our results reveal a
mode of action of PDL1 in cancer cells as a first line
of defense against IFN cytotoxicity
Chimeric switch receptor: switching for improved adoptive T-cell therapy against cancers
EP08.01-090 Association of Gender and Outcomes in Patients With Advanced NSCLC Treated With Immunotherapy Alone or in Combination With Chemotherapy Upfront
EP08.01-091 Association of dNLR Score with Outcomes in Patients with Advanced NSCLC Under Immunotherapy Alone +/- Chemotherapy Upfront
OA07.06 Second Line Treatment Outcomes After Progression on Immunotherapy Plus Chemotherapy (IO-CT) In Advanced Non-small Cell Lung Cancer (aNSCLC)
INTRODUCTION : The combination of IO-CT has become the standard of care for patients with aNSCLC with a low or intermediate programmed death-ligand 1 (PD-L1) expression (<50%), and an option for patients with high PDL1 (≥50%) expression. There are no data available on the subsequent line (L2) outcomes after IO-CT. We aimed to assess the outcomes of various L2 treatments after IO-CT in aNSCLC. [...
Profound reprogramming towards stemness in pancreatic cancer cells as adaptation to AKT inhibition
Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways
by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic
adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation
to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer
cells were studied. Following silencing, cancer cells remained quiescent for long periods of time,
after which they recovered proliferative capacities. Adaptation caused profound proteomic changes
largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of
distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced.
The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through
C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted
CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators
of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of
AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in
pre-clinical models
Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics
Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an
acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on
radiological evaluation present important technical limitations. No biomarkers have been identified
yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy
after progression to platinum-based therapy were prospectively studied. Samples from peripheral
blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood
mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified
by flow cytometry and correlated with HPD as identified with radiological criteria. A strong
expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and
second cycle of therapy was observed in HPD patients. After normalizing, the proportion of
posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the
rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD
progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3
identified HPD with 82% specificity and 70% sensitivity. An increase of CD28− CD4 T lymphocytes ≥
1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR)
was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients
(median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03,
p = 0.0126). A strong expansion of CD28− CD4 lymphocytes in peripheral blood within the first
cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in
clinical practice and complements radiological evaluation
Profound reprogramming towards stemness in pancreatic cancer cells as adaptation to AKT inhibition
Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways
by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic
adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation
to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer
cells were studied. Following silencing, cancer cells remained quiescent for long periods of time,
after which they recovered proliferative capacities. Adaptation caused profound proteomic changes
largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of
distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced.
The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through
C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted
CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators
of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of
AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in
pre-clinical models
Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics
Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an
acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on
radiological evaluation present important technical limitations. No biomarkers have been identified
yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy
after progression to platinum-based therapy were prospectively studied. Samples from peripheral
blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood
mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified
by flow cytometry and correlated with HPD as identified with radiological criteria. A strong
expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and
second cycle of therapy was observed in HPD patients. After normalizing, the proportion of
posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the
rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD
progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3
identified HPD with 82% specificity and 70% sensitivity. An increase of CD28− CD4 T lymphocytes ≥
1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR)
was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients
(median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03,
p = 0.0126). A strong expansion of CD28− CD4 lymphocytes in peripheral blood within the first
cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in
clinical practice and complements radiological evaluation