Controlled experimental generation of perturbed high-order Ince-Gaussian laser modes.

We present an experimental approach for generating perturbed high-order Ince-Gaussian laser modes by transforming the low and moderate-intensity lobes of high-order Ince-Gaussian (IG) modes into high-intensity lobes and vice versa. This perturbation reshuffles optical energy among the different lobes and generates new, to the best of our knowledge, modulated Ince-Gaussian (MIG) modes. Computer-generated holograms displayed over spatial light modulators were used to modulate the IGMs. Compared to IG modes, MIG modes are generated precisely in a sense that enhances the IG modes and provides a maximum number of highly intense lobes in a particular mode. That enables the newly generated MIG modes to be utilized more efficiently than IG modes in applications such as particle manipulation and optical trapping of microparticles, which exploit highly intense lobes.

Creation of pure longitudinal super-oscillatory spot.

We present a method that creates a super-oscillatory focal spot of a tightly focused radially polarized beam using the concept of a phase mask. Using vector diffraction theory, we report a super-oscillatory focal spot that is much smaller than the diffraction limit and the super-oscillation criterion. The proposed mask works as a special polarization filter that enhances the longitudinal component and filters out the transverse component of radial polarization at focus, permitting the creation of a pure longitudinal super-oscillatory focal spot.

Controllable experimental modulation of high-order Laguerre-Gaussian laser modes.

High-order helical and sinusoidal Laguerre-Gaussian (LG) laser modes have uneven energy distribution among their multiple concentric vortex core rings and lobes, respectively. Here, we explore an experimental method to reshuffle the optical energy among their multiple concentric vortex core rings and lobes of high-order LG modes in a controllable manner. We numerically designed a diffractive optical element displayed over a spatial light modulator to rearrange optical energy among multiple concentric vortex core rings. This changes outer low-intensity concentric vortex core rings into high-intensity vortex core rings of high-order helical LG modes at the Fourier plane. The precise generation of a high-order modulated helical LG laser mode has a maximum number of highly intense concentric vortex core rings compared to known standard helical LG modes. Further, this method is extended to high-order sinusoidal LG modes consisting of both low- and high-intensity lobes to realize modulated sinusoidal LG modes with a maximum number of highly intense lobes in a controllable manner. We envisage that the modulated helical and sinusoidal high-order LG modes may surpass standard LG modes in many applications where highly intense rings and lobes are crucial, as in particle manipulation of micro- and nanoparticles, and optical lithography.

Super-oscillatory spots with different inhomogeneous linear polarized states.

We present the formation of super-oscillatory (SO) spots by tightly focusing the inhomogeneous linear polarized beam of different polarization states. At the entrance pupil of the focusing lens, a suitable phase manipulation in the incident beam results in a small super-oscillatory spot. Our numerical study based on the vectorial diffraction theory shows that SO spots of controllable size and various polarization combinations are possible. We also discuss the effect of the different polarization patterns of the incident beam on the size and energy distribution of the generated SO spots, which are potentially valuable for the orientation determination of single molecules and polarization-resolved imaging. This study reveals more influence of polarization states on the different components of the focused beam under the utilization of the proposed method rather than the usual tight focusing conditions.

SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms.

SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.

Tumor Intrinsic Efficacy by SHP2 and RTK Inhibitors in KRAS-Mutant Cancers.

KRAS, an oncogene mutated in nearly one third of human cancers, remains a pharmacologic challenge for direct inhibition except for recent advances in selective inhibitors targeting the G12C variant. Here, we report that selective inhibition of the protein tyrosine phosphatase, SHP2, can impair the proliferation of KRAS-mutant cancer cells in vitro and in vivo using cell line xenografts and primary human tumors. In vitro, sensitivity of KRAS-mutant cells toward the allosteric SHP2 inhibitor, SHP099, is not apparent when cells are grown on plastic in 2D monolayer, but is revealed when cells are grown as 3D multicellular spheroids. This antitumor activity is also observed in vivo in mouse models. Interrogation of the MAPK pathway in SHP099-treated KRAS-mutant cancer models demonstrated similar modulation of p-ERK and DUSP6 transcripts in 2D, 3D, and in vivo, suggesting a MAPK pathway-dependent mechanism and possible non-MAPK pathway-dependent mechanisms in tumor cells or tumor microenvironment for the in vivo efficacy. For the KRASG12C MIAPaCa-2 model, we demonstrate that the efficacy is cancer cell intrinsic as there is minimal antiangiogenic activity by SHP099, and the effects of SHP099 is recapitulated by genetic depletion of SHP2 in cancer cells. Furthermore, we demonstrate that SHP099 efficacy in KRAS-mutant models can be recapitulated with RTK inhibitors, suggesting RTK activity is responsible for the SHP2 activation. Taken together, these data reveal that many KRAS-mutant cancers depend on upstream signaling from RTK and SHP2, and provide a new therapeutic framework for treating KRAS-mutant cancers with SHP2 inhibitors.